1.
Anaphase I
–
This process occurs in all sexually reproducing single-celled and multicellular eukaryotes, including animals, plants, and fungi. Errors in meiosis resulting in aneuploidy are the known cause of miscarriage. In meiosis, DNA replication is followed by two rounds of division to produce four potential daughter cells, each with half the number of chromosomes as the original parent cell. The two meiotic divisions are known as Meiosis I and Meiosis II and this S-phase can be referred to as premeiotic S-phase or meiotic S-phase. Immediately following DNA replication, meiotic cells enter a prolonged G2-like stage known as meiotic prophase, a subset of recombination events results in crossovers, which create physical links known as chiasmata between the homologous chromosomes. During Meiosis II, the cohesion between sister chromatids is released and they segregate from one another, as during mitosis, in some cases all four of the meiotic products form gametes such as sperm, spores, or pollen. In female animals, three of the four meiotic products are eliminated by extrusion into polar bodies, and only one cell develops to produce an ovum. Because the number of chromosomes is halved during meiosis, gametes can fuse to form a zygote that contains two copies of each chromosome, one from each parent. Thus, alternating cycles of meiosis and fertilization enable sexual reproduction, for example, diploid human cells contain 23 pairs of chromosomes including 1 pair of sex chromosomes, half of maternal origin and half of paternal origin. Meiosis produces haploid gametes that contain one set of 23 chromosomes, when two gametes fuse, the resulting zygote is once again diploid, with the mother and father each contributing 23 chromosomes. This same pattern, but not the number of chromosomes. First, the cell undergoes DNA replication, so each homolog now consists of two sister chromatids. Then each set of homologs pair with other and exchange DNA by homologous recombination leading to physical connections between the homologs. In the first meiotic division, the homologs are segregated to daughter cells by the spindle apparatus. The cells then proceed to a division without an intervening round of DNA replication. The sister chromatids are segregated to daughter cells to produce a total of four haploid cells. Female animals employ a variation on this pattern and produce one large ovum. Because of recombination, an individual chromatid can consist of a new combination of maternal and paternal DNA, furthermore, an individual gamete can include an assortment of maternal, paternal, and recombinant chromatids
2.
Anaphase II
–
This process occurs in all sexually reproducing single-celled and multicellular eukaryotes, including animals, plants, and fungi. Errors in meiosis resulting in aneuploidy are the known cause of miscarriage. In meiosis, DNA replication is followed by two rounds of division to produce four potential daughter cells, each with half the number of chromosomes as the original parent cell. The two meiotic divisions are known as Meiosis I and Meiosis II and this S-phase can be referred to as premeiotic S-phase or meiotic S-phase. Immediately following DNA replication, meiotic cells enter a prolonged G2-like stage known as meiotic prophase, a subset of recombination events results in crossovers, which create physical links known as chiasmata between the homologous chromosomes. During Meiosis II, the cohesion between sister chromatids is released and they segregate from one another, as during mitosis, in some cases all four of the meiotic products form gametes such as sperm, spores, or pollen. In female animals, three of the four meiotic products are eliminated by extrusion into polar bodies, and only one cell develops to produce an ovum. Because the number of chromosomes is halved during meiosis, gametes can fuse to form a zygote that contains two copies of each chromosome, one from each parent. Thus, alternating cycles of meiosis and fertilization enable sexual reproduction, for example, diploid human cells contain 23 pairs of chromosomes including 1 pair of sex chromosomes, half of maternal origin and half of paternal origin. Meiosis produces haploid gametes that contain one set of 23 chromosomes, when two gametes fuse, the resulting zygote is once again diploid, with the mother and father each contributing 23 chromosomes. This same pattern, but not the number of chromosomes. First, the cell undergoes DNA replication, so each homolog now consists of two sister chromatids. Then each set of homologs pair with other and exchange DNA by homologous recombination leading to physical connections between the homologs. In the first meiotic division, the homologs are segregated to daughter cells by the spindle apparatus. The cells then proceed to a division without an intervening round of DNA replication. The sister chromatids are segregated to daughter cells to produce a total of four haploid cells. Female animals employ a variation on this pattern and produce one large ovum. Because of recombination, an individual chromatid can consist of a new combination of maternal and paternal DNA, furthermore, an individual gamete can include an assortment of maternal, paternal, and recombinant chromatids
3.
Ancient Greek
–
Ancient Greek includes the forms of Greek used in ancient Greece and the ancient world from around the 9th century BC to the 6th century AD. It is often divided into the Archaic period, Classical period. It is antedated in the second millennium BC by Mycenaean Greek, the language of the Hellenistic phase is known as Koine. Koine is regarded as a historical stage of its own, although in its earliest form it closely resembled Attic Greek. Prior to the Koine period, Greek of the classic and earlier periods included several regional dialects, Ancient Greek was the language of Homer and of fifth-century Athenian historians, playwrights, and philosophers. It has contributed many words to English vocabulary and has been a subject of study in educational institutions of the Western world since the Renaissance. This article primarily contains information about the Epic and Classical phases of the language, Ancient Greek was a pluricentric language, divided into many dialects. The main dialect groups are Attic and Ionic, Aeolic, Arcadocypriot, some dialects are found in standardized literary forms used in literature, while others are attested only in inscriptions. There are also several historical forms, homeric Greek is a literary form of Archaic Greek used in the epic poems, the Iliad and Odyssey, and in later poems by other authors. Homeric Greek had significant differences in grammar and pronunciation from Classical Attic, the origins, early form and development of the Hellenic language family are not well understood because of a lack of contemporaneous evidence. Several theories exist about what Hellenic dialect groups may have existed between the divergence of early Greek-like speech from the common Proto-Indo-European language and the Classical period and they have the same general outline, but differ in some of the detail. The invasion would not be Dorian unless the invaders had some relationship to the historical Dorians. The invasion is known to have displaced population to the later Attic-Ionic regions, the Greeks of this period believed there were three major divisions of all Greek people—Dorians, Aeolians, and Ionians, each with their own defining and distinctive dialects. Often non-west is called East Greek, Arcadocypriot apparently descended more closely from the Mycenaean Greek of the Bronze Age. Boeotian had come under a strong Northwest Greek influence, and can in some respects be considered a transitional dialect, thessalian likewise had come under Northwest Greek influence, though to a lesser degree. Most of the dialect sub-groups listed above had further subdivisions, generally equivalent to a city-state and its surrounding territory, Doric notably had several intermediate divisions as well, into Island Doric, Southern Peloponnesus Doric, and Northern Peloponnesus Doric. The Lesbian dialect was Aeolic Greek and this dialect slowly replaced most of the older dialects, although Doric dialect has survived in the Tsakonian language, which is spoken in the region of modern Sparta. Doric has also passed down its aorist terminations into most verbs of Demotic Greek, by about the 6th century AD, the Koine had slowly metamorphosized into Medieval Greek
4.
Mitosis
–
In cell biology, mitosis is a part of the cell cycle when replicated chromosomes are separated into two new nuclei. Mitosis and cytokinesis together define the phase of an animal cell cycle—the division of the mother cell into two daughter cells genetically identical to each other. The process of mitosis is divided into stages corresponding to the completion of one set of activities and these stages are prophase, prometaphase, metaphase, anaphase, and telophase. During mitosis, the chromosomes, which have already duplicated, condense, the result is two genetically identical daughter nuclei. The rest of the cell may then continue to divide by cytokinesis to produce two daughter cells, producing three or more daughter cells instead of normal two is a mitotic error called tripolar mitosis or multipolar mitosis. Other errors during mitosis can induce apoptosis or cause mutations, certain types of cancer can arise from such mutations. Mitosis occurs only in eukaryotic cells, prokaryotic cells, which lack a nucleus, divide by a different process called binary fission. Most animal cells undergo a change, known as mitotic cell rounding. Most human cells are produced by cell division. Important exceptions include the gametes – sperm and egg cells – which are produced by meiosis, german zoologist Otto Bütschli might have claimed the discovery of the process presently known as mitosis, a term coined by Walther Flemming in 1882. Mitosis was discovered in frog, rabbit, and cat cornea cells in 1873, the term is derived from the Greek word μίτος mitos warp thread. The primary result of mitosis and cytokinesis is the transfer of a parent cells genome into two daughter cells, the genome is composed of a number of chromosomes—complexes of tightly coiled DNA that contain genetic information vital for proper cell function. Because each resultant daughter cell should be identical to the parent cell. This occurs during the S phase of interphase, chromosome duplication results in two identical sister chromatids bound together by cohesin proteins at the centromere. When mitosis begins, the chromosomes condense and become visible, in some eukaryotes, for example animals, the nuclear envelope, which segregates the DNA from the cytoplasm, disintegrates into small vesicles. The nucleolus, which makes ribosomes in the cell, also disappears, microtubules project from opposite ends of the cell, attach to the centromeres, and align the chromosomes centrally within the cell. The microtubules then contract to pull the chromatids of each chromosome apart. Sister chromatids at this point are called daughter chromosomes, as the cell elongates, corresponding daughter chromosomes are pulled toward opposite ends of the cell and condense maximally in late anaphase
5.
Metaphase
–
Metaphase is a stage of mitosis in the eukaryotic cell cycle in which chromosomes are at their second-most condensed and coiled stage. These chromosomes, carrying information, align in the equator of the cell before being separated into each of the two daughter cells. Metaphase accounts for approximately 4% of the cell cycles duration, preceded by events in prometaphase and followed by anaphase, microtubules formed in prophase have already found and attached themselves to kinetochores in metaphase. In metaphase, the centromeres of the chromosomes convene themselves on the metaphase plate, in certain types of cells, chromosomes do not line up at the metaphase plate and instead move back and forth between the poles randomly, only roughly lining up along the middleline. One of the cell cycle checkpoints occurs during prometaphase and metaphase, only after all chromosomes have become aligned at the metaphase plate, when every kinetochore is properly attached to a bundle of microtubules, does the cell enter anaphase. Such a signal creates the mitotic spindle checkpoint and this would be accomplished by regulation of the anaphase-promoting complex, securin, and separase. The analysis of chromosomes is one of the main tools of classical cytogenetics. Chromosomes are condensed and highly coiled in metaphase, which makes them most suitable for visual analysis, Metaphase chromosomes make the classical picture of chromosomes. For classical cytogenetic analyses, cells are grown in short term culture, further they are used for slide preparation and banding of chromosomes to be visualised under microscope to study structure and number of chromosomes. Staining of the slides, often with Giemsa or Quinacrine, produces a pattern of in total up to several hundred bands, normal metaphase spreads are used in methods like FISH and as a hybridization matrix for comparative genomic hybridization experiments. Malignant cells from solid tumors or leukemia samples can also be used for analysis to generate metaphase preparations. Interphase Prophase Anaphase Telophase Media related to Metaphase at Wikimedia Commons
6.
Chromosome
–
A chromosome is a DNA molecule with part or all of the genetic material of an organism. Prokaryotes usually have one single circular chromosome, whereas most eukaryotes are diploid, chromosomes in eukaryotes are composed of chromatin fiber. Chromatin fiber is made of nucleosomes, a nucleosome is a histone octamer with part of a longer DNA strand attached to and wrapped around it. Chromatin fiber, together with associated proteins is known as chromatin, chromatin is present in most cells, with a few exceptions, for example, red blood cells. Occurring only in the nucleus of cells, chromatin contains the vast majority of DNA, except for a small amount inherited maternally. Chromosomes are normally visible under a microscope only when the cell is undergoing the metaphase of cell division. Before this happens every chromosome is copied once, and the copy is joined to the original by a centromere resulting in an X-shaped structure, the original chromosome and the copy are now called sister chromatids. During metaphase, when a chromosome is in its most condensed state, in this highly condensed form chromosomes are easiest to distinguish and study. In prokaryotic cells, chromatin occurs free-floating in cytoplasm, as these cells lack organelles, the main information-carrying macromolecule is a single piece of coiled double-helix DNA, containing many genes, regulatory elements and other noncoding DNA. The DNA-bound macromolecules are proteins that serve to package the DNA, chromosomes vary widely between different organisms. Some species such as certain bacteria also contain plasmids or other extrachromosomal DNA and these are circular structures in the cytoplasm that contain cellular DNA and play a role in horizontal gene transfer. Chromosomal recombination during meiosis and subsequent sexual reproduction plays a significant role in genetic diversity. In prokaryotes and viruses, the DNA is often densely packed and organized, in the case of archaea, by homologs to eukaryotic histones, small circular genomes called plasmids are often found in bacteria and also in mitochondria and chloroplasts, reflecting their bacterial origins. Some use the term chromosome in a sense, to refer to the individualized portions of chromatin in cells. However, others use the concept in a sense, to refer to the individualized portions of chromatin during cell division. The word chromosome comes from the Greek χρῶμα and σῶμα, describing their strong staining by particular dyes, schleiden, Virchow and Bütschli were among the first scientists who recognized the structures now so familiar to everyone as chromosomes. The term was coined by von Waldeyer-Hartz, referring to the term chromatin, in a series of experiments beginning in the mid-1880s, Theodor Boveri gave the definitive demonstration that chromosomes are the vectors of heredity. His two principles were the continuity of chromosomes and the individuality of chromosomes and it is the second of these principles that was so original
7.
Securin
–
Securin is a protein involved in control of the metaphase-anaphase transition and anaphase onset. Securin is initially present in the cytoplasm and binds to separase, separase is vital for onset of anaphase. This securin-separase complex is maintained when securin is phosphorylated by Cdk1, when bound to securin, separase is not functional. In addition, both securin and separase are well-conserved proteins, note that separase cannot function without initially forming the securin-separase complex. This is because securin helps properly fold separase into the functional conformation, however, yeast does not appear to require securin to form functional separase as anaphase occurs in yeast with a securin deletion mutation. Securin has 5 known phosphorylation sites that are targets of Cdk1,2 sites at the N-terminal in the Ken-Box and D-box region are known to affect APC recognition and ubiquitination, to initiate the onset of anaphase, securin is dephosphorylated by Cdc14 and other phosphatases. Dephosphorylated securin is recognized by the Anaphase-Promoting Complex bound primarily to Cdc20, the APCCdc20 complex ubiquitinates securin and targets it for degradation. This results in free separase that is able to destroy cohesin and it is thought that securin integrates multiple regulatory inputs to make separase activation switch-like, resulting in sudden, coordinated anaphase. This likely involves a network with several loops, including positive feedback which leads to switch-like behavior. One proposed signaling pathway generating switch-like behavior contains a positive feedback loop for activation of Cdc14 by separase, in addition, these mutant strains exhibited very high rates of mis-segregation compared to normal behavior. Switch-like characteristics are necessary to trigger quick, coordinated chromosomal segregation in anaphase and this means that strong inactivation of separase by securin followed by sudden, rapid destruction of securin and activation of separase is vital for proper anaphase. Overall, securin and separase act in an anaphase-regulating network, figure 4 depicts a potential network diagram
8.
Protease
–
A protease is any enzyme that performs proteolysis, protein catabolism by hydrolysis of peptide bonds. Proteases have evolved multiple times, and different classes of protease can perform the reaction by completely different catalytic mechanisms. Proteases can be found in Animalia, Plantae, Fungi, Bacteria, Archaea, the threonine and glutamic-acid proteases were not described until 1995 and 2004 respectively. One way to make a nucleophile is by a catalytic triad, a seventh catalytic type of proteolytic enzymes, asparagine peptide lyase, was described in 2011. Its proteolytic mechanism is unusual since, rather than hydrolysis, it performs an elimination reaction, during this reaction, the catalytic asparagine forms a cyclic chemical structure that cleaves itself at asparagine residues in proteins under the right conditions. Given its fundamentally different mechanism, its inclusion as a peptidase may be debatable, an up-to-date classification of protease evolutionary superfamilies is found in the MEROPS database. In this database, proteases are classified firstly by clan based on structure, mechanism, within each clan, proteases are classified into families based on sequence similarity. Each family may contain hundreds of related proteases. Currently more than 50 clans are known, each indicating an independent evolutionary origin of proteolysis, alternatively, proteases may be classified by the optimal pH in which they are active, Acid proteases Neutral proteases involved in type 1 hypersensitivity. Here, it is released by mast cells and causes activation of complement, basic proteases Proteases are involved in digesting long protein chains into shorter fragments by splitting the peptide bonds that link amino acid residues. Some detach the terminal amino acids from the chain, others attack internal peptide bonds of a protein. Catalysis is achieved by one of two mechanisms, Aspartic, glutamic and metallo- proteases activate a water molecule performs a nucleophilic attack on the peptide bond to hydrolyse it. Serine, threonine and cysteine proteases use a nucleophilic residue and that residue performs a nucleophilic attack to covalently link the protease to the substrate protein, releasing the first half of the product. This covalent acyl-enzyme intermediate is hydrolysed by activated water to complete catalysis by releasing the second half of the product. Proteolysis can be highly promiscuous such that a range of protein substrates are hydrolysed. This is the case for digestive enzymes such as trypsin which have to be able to cleave the array of proteins ingested into smaller peptide fragments, promiscuous proteases typically bind to a single amino acid on the substrate and so only have specificity for that residue. For example, trypsin is specific for the sequences. K\, conversely some proteases are highly specific and only cleave substrates with a certain sequence. Blood clotting and viral polyprotein processing requires this level of specificity in order to achieve precise cleavage events and this is achieved by proteases having a long binding cleft or tunnel with several pockets along it which bind the specified residues
9.
Separase
–
In humans, separin is encoded by the ESPL1 gene. In S. cerevisiae, separase is encoded by the esp1 gene, Esp1 was discovered by Kim Nasmyth and coworkers in 1998. Stable cohesion between sister chromatids before anaphase and their separation during anaphase are critical for cell division. In vertebrates, sister chromatid cohesion is released in 2 steps via distinct mechanisms, the first step involves phosphorylation of STAG1 or STAG2 in the cohesin complex. The second step involves cleavage of the cohesin subunit SCC1 by separase, in S. cerevisiae, Esp1 is coded by ESP1 and is regulated by the securin Pds1. The proteins that bind the two chromatids, disallowing any premature sister chromatid separation, are a part of the cohesin protein family. One of these cohesin proteins crucial for sister chromatid cohesion is Scc1, Esp1 is a separase protein that cleaves the cohesin subunit Scc1, allowing sister chromatids to separate at the onset of anaphase during mitosis. When the cell is not dividing, separase is prevented from cleaving cohesin through its association with another protein, securin and this provides two layers of negative regulation to prevent inappropriate cohesin cleavage. Note that separase cannot function without initially forming the complex in most organisms. This is because securin helps properly fold separase into the functional conformation, however, yeast does not appear to require securin to form functional separase because anaphase occurs in yeast even with a securin deletion. On the signal for anaphase, securin is ubiquitinated and hydrolysed, active separase can then cleave Scc1 for release of the sister chromatids. Separase initiates the activation of Cdc14 in early anaphase and Cdc14 has been found to dephosphorylate securin, the presence of this positive feedback loop offers a potential mechanism for giving anaphase a more switch-like behavior
10.
Cohesin
–
Cohesin is a protein complex that regulates the separation of sister chromatids during cell division, either mitosis or meiosis. Cohesins hold sister chromatids together after DNA replication until anaphase when removal of cohesin leads to separation of sister chromatids, Cohesin is a multi-subunit protein complex, made up of four core subunits, two SMC proteins, an alpha-kleisin, and an orthologue of the yeast Scc3 protein. Smc1 and Smc3 are members of the Structural Maintenance of Chromosomes family, SMC proteins have two main structural characteristics, an ATP-binding cassette-like head domain with ATPase activity and a hinge domain that allows dimerization of SMCs. The head and the domains are connected to each other via long anti-parallel coiled coils. The dimer is present in a V-shaped form, connected by the hinges, upon ATP binding, the two head domains in the dimer bind to each other, forming a ring structure. ATP hydrolysis can therefore trigger opening and closing of the ring, Scc1 and Scc3 bind the ATPase domains of Smc1 and Smc3 stabilizing the ring structure. The amino and carboxy terminus of Scc1 bind Smc1 and Smc3, once Scc1 binds the SMC proteins, Scc3 can also associate by binding with the C-terminal region of Scc1. When Scc1 binds on both Smc1 and Smc3, the complex forms a closed ring structure. When it binds to one of the SMC proteins, the complex forms an open ring. While some studies support the idea of a model, the model is inconsistent with a number of experimental observations. The cohesin ring has many functions,1 and it is used to keep the sister chromatids connected with each other during metaphase ensuring that during mitosis, each sister chromatid segregates to opposite poles. It facilitates spindle attachment onto chromosomes and it facilitates DNA repair by recombination. Recently many novel functions of cohesin have been discovered in different cellular processes. The anaphase promoting complex associated to Cdc20 cleaves the securin, which holds the sister chromatids together, securin is cleaved at anaphase, following APC/C-cdc20 mediated degradation, and it renders separase to cleave the kleisin subunit. Dissociation of sister chromatids cohesion defines anaphase onset, which two sets of identical chromosomes at each pole of the cell. Then the two daughter cells separate, and a new round of the cell cycle starts in each one. Therefore, when the division process will end, each daughter cell will receive a complete set of organelles. At the same time, during S phase all cells must duplicate their DNA very precisely and it is not clear how the cohesion ring links sister chromatids together
11.
Kinetochore
–
Kinetochore, protein structure found at the centromere of a chromatid to which microtubules attach to during cell division. The kinetochore is a structure on chromatids where the spindle fibers attach during cell division to pull sister chromatids apart. Their proteins help to hold the sister chromatids together and also play a role in chromosome editing, the kinetochore forms in eukaryotes, assembles on the centromere and links the chromosome to microtubule polymers from the mitotic spindle during mitosis and meiosis. Monocentric organisms, including vertebrates, fungi, and most plants, have a single region on each chromosome which assembles one kinetochore. Holocentric organisms, such as nematodes and some plants, assemble a kinetochore along the length of a chromosome. Kinetochores start, control, and supervise the movements of chromosomes during cell division. Thus, the kinetochore is essential for the segregation that is classically associated with mitosis and meiosis. Even the simplest kinetochores consist of more than 19 different proteins, many of these proteins are conserved between eukaryotic species, including a specialized histone H3 variant which helps the kinetochore associate with DNA. Other proteins in the kinetochore attach it to the microtubules of the mitotic spindle, there are also motor proteins, including both dynein and kinesin, which generate forces that move chromosomes during mitosis. On the other hand, MTs are metastable polymers made of α- and β-tubulin, MTs are highly dynamic structures, whose behavior is integrated with kinetochore function to control chromosome movement and segregation. The kinetochore is composed of layers, observed initially by conventional fixation and staining methods of electron microscopy. The deepest layer in the kinetochore is the plate, which is organized on a chromatin structure containing nucleosomes presenting a specialized histone, auxiliary proteins. DNA organization in the centromere is one of the least known aspects in vertebrate kinetochores, the inner plate appears like a discrete heterochromatin domain throughout the cell cycle. Outside the inner plate we find the outer plate, composed mostly by proteins and this structure is assembled in the surface of the chromosomes when the nuclear envelope breaks down. The outer plate in vertebrate kinetochores contains about 20 anchoring sites for MTs ends, the outermost domain in the kinetochore forms a fibrous corona, which can be visualized by conventional microscopy, yet only in absence of MTs. This corona is formed by a network of resident and temporary proteins implicated in the spindle checkpoint, in MTs anchoring. During mitosis, each sister chromatid forming the complete chromosome has its own kinetochore, distinct sister kinetochores can be observed at first at the end of G2 phase in cultured mammalian cells. These early kinetochores show a mature laminar structure before the nuclear envelope breaks down, yet no simple linear route can describe the data obtained so far
12.
Spindle apparatus
–
In cell biology, the spindle apparatus refers to the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. Besides chromosomes, the apparatus is composed of hundreds of proteins. Microtubules comprise the most abundant components of the machinery, attachment of microtubules to chromosomes is mediated by kinetochores, which actively monitor spindle formation and prevent premature anaphase onset. Microtubule polymerization and depolymerization dynamics drive chromosome congression, once every chromosome is bi-oriented, anaphase commences and cohesin, which couples sister chromatids, is severed, permitting the transit of the sister chromatids to opposite poles. The spindle apparatus is vaguely ellipsoid in cross section and tapers at the ends, in the wide middle portion, known as the spindle midzone, antiparallel microtubules are bundled by kinesins. At the pointed ends, known as spindle poles, microtubules are nucleated by the centrosomes in most animal cells, acentrosomal or anastral spindles lack centrosomes or asters at the spindle poles, respectively, and occur for example during female meiosis in most animals. In this instance, a Ran GTP gradient is the regulator of spindle microtubule organization. In fungi, spindles form between spindle pole bodies embedded in the envelope, which does not break down during mitosis. Microtubule-associated proteins associate with microtubules at the midzone and the poles to regulate their dynamics. γ-tubulin is a specialized tubulin variant that assembles into a complex called γ-TuRC which nucleates polymerization of α/β tubulin heterodimers into microtubules. The growing ends of microtubules are protected against catastrophe by the action of plus-end microtubule tracking proteins to promote their association with kinetochores at the midzone, cLIP170 was shown to localize near microtubule plus-ends in HeLa cells and to accumulate in kinetochores during prometaphase. CLIP-associated proteins like CLASP1 in humans have also shown to localize to plus-ends. Plus-end polymerization may be moderated by the EB1 protein, which directly binds the growing ends of microtubules and coordinates the binding of other +TIPs. MCAK localizes to the tips of microtubules at kinetochores where it can trigger catastrophe in direct competition with stabilizing +TIP activity. These proteins harness the energy of ATP hydrolysis to induce destabilizing conformational changes in protofilament structure that cause kinesin release, loss of their activity results in numerous mitotic defects. Additional microtubule destabilizing proteins include Op18/stathmin and katanin which have roles in remodeling the mitotic spindle as well as promoting chromosome segregation during anaphase. The activities of these MAPs are carefully regulated to maintain proper microtubule dynamics during spindle assembly, with many of these serving as Aurora. The precise orientation of this complex is required to ensure accurate chromosome segregation, however, it remains unclear how the spindle becomes organized
13.
Telophase
–
Telophase is the final stage in both meiosis and mitosis in a eukaryotic cell. During telophase, the effects of prophase and prometaphase are reversed, the chromosomes reach the poles as the nuclear membranes re-form around each set of chromatids, the nucleoli also reappear. The remaining spindle microtubules begin to depolymerize, the chromosomes also unwind back into the expanded chromatin that is present during interphase. Telophase accounts for approximately 2% of the cell cycles duration, cytokinesis typically begins before late telophase. In land plant cells, vesicles derived from the Golgi apparatus move to the middle of the cell along a microtubule scaffold called the phragmoplast and this structure directs packets of cell wall materials which coalesce into a disk-shaped structure called a cell plate. The cell plate grows out centrifugally and eventually develops into a cell wall. Interphase Prophase Metaphase Anaphase Media related to Telophase at Wikimedia Commons
14.
Cell cycle
–
The cell cycle or cell-division cycle is the series of events that take place in a cell leading to its division and duplication of its DNA to produce two daughter cells. In bacteria, which lack a nucleus, the cell cycle is divided into the B, C. The B period extends from the end of cell division to the beginning of DNA replication, DNA replication occurs during the C period. The D period refers to the stage between the end of DNA replication and the splitting of the cell into two daughter cells. In cells with a nucleus, as in eukaryotes, the cycle is also divided into three periods, interphase, the mitotic phase, and cytokinesis. During interphase, the cell grows, accumulating nutrients needed for mitosis, preparing it for cell division, during the mitotic phase, the chromosomes separate. During the final stage, cytokinesis, the chromosomes and cytoplasm separate into two new daughter cells, to ensure the proper division of the cell, there are control mechanisms known as cell cycle checkpoints. After cell division, each of the cells begin the interphase of a new cycle. The cell cycle consists of four phases, G1 phase, S phase, G2 phase. Activation of each phase is dependent on the progression and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase, after cell division, each of the daughter cells begin the interphase of a new cycle. G0 is a phase where the cell has left the cycle and has stopped dividing. The cell cycle starts with this phase, the word post-mitotic is sometimes used to refer to both quiescent and senescent cells. Non proliferative cells in multicellular eukaryotes generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time and this is very common for cells that are fully differentiated. Cellular senescence occurs in response to DNA damage and external stress, some cells enter the G0 phase semi-permanently, and are considered post-mitotic e. g. some liver, kidney, stomach cells. Many cells do not enter G0 and continue to divide throughout an organisms life, before a cell can enter cell division, it needs to take in nutrients. All of the preparations are done during interphase, interphase is a series of changes that takes place in a newly formed cell and its nucleus, before it becomes capable of division again. It is also called preparatory phase or intermitosis, previously it was called resting stage because there is no apparent activity related to cell division. Typically interphase lasts for at least 90% of the total time required for the cell cycle
15.
Cyclin
–
Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase enzymes. Cyclins were originally discovered by R. Timothy Hunt in 1982 while studying the cell cycle of sea urchins, in an interview for The Life Scientific hosted by Jim Al-Khalili, R. Timothy Hunt explained that the name cyclin was originally named after his hobby cycling. It was only after the naming did its importance in the cell cycle become apparent, as it was appropriate the name stuck. R. Timothy Hunt, By the way, the cyclin, which I coined, was really a joke, its because I liked cycling so much at the time. Cyclins were originally named because their concentration varies in a fashion during the cell cycle. A cyclin forms a complex with Cdk, which begins to activate the Cdk, complex formation results in activation of the Cdk active site. Cyclins themselves have no enzymatic activity but have binding sites for some substrates, Cyclins, when bound with the dependent kinases, such as the p34/cdc2/cdk1 protein, form the maturation-promoting factor. MPFs activate other proteins through phosphorylation and these phosphorylated proteins, in turn, are responsible for specific events during cycle division such as microtubule formation and chromatin remodeling. Cyclins can be divided into four classes based on their behavior in the cycle of vertebrate somatic cells and yeast cells, G1 cyclins, G1/S cyclins, S cyclins. This division is useful when talking about most cell cycles, G1/S Cyclins rise in late G1 and fall in early S phase. The Cdk- G1/S cyclin complex begins to induce the initial processes of DNA replication, the cyclins also promote other activities to progress the cell cycle, such as centrosome duplication in vertebrates or spindle pole body in yeast. The rise in presence of G1/S cyclins is paralleled by a rise in S cyclins, G1 cyclins do not behave like the other cyclins, in that the concentrations increase gradually, throughout the cell cycle based on cell growth and the external growth-regulatory signals. The presence of G cyclins coordinate cell growth with the entry to a new cell cycle, S cyclins bind to Cdk and the complex directly induces DNA replication. The levels of S cyclins remain high, not only throughout S phase, M cyclin concentrations rise as the cell begins to enter mitosis and the concentrations peak at metaphase. Cell changes in the cell cycle like the assembly of mitotic spindles, the destruction of M cyclins during metaphase and anaphase, after the Spindle Assembly Checkpoint is satisfied, causes the exit of mitosis and cytokinesis. Cyclins are generally different from each other in primary structure. However, all members of the family are similar in 100 amino acids that make up the cyclin box. Cyclins contain two domains of a similar fold, the first located at the N-terminus and the second at the C-terminus
16.
Ubiquitin
–
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. It was discovered in 1975 in Israel by Gideon Goldstein and further characterized throughout the 1970s and 1980s, there are four genes in the human genome that produce ubiquitin, UBB, UBC, UBA52 and RPS27A. The addition of ubiquitin to a protein is called ubiquitination or ubiquitylation. The protein modifications can be either a single protein or a chain of ubiquitin. The ubiquitination bonds are formed with one of the seven lysine residues as well as the very N-terminal methionine from the ubiquitin molecule. These linking residues are represented by a K or M and a number, first, a ubiquitin molecule is bonded by its C-terminus to a specific lysine residue on the target protein. This process repeats several times, leading to the addition of several ubiquitins, the discovery that ubiquitin chains target proteins to the proteasome, which degrades and recycles proteins, was honored with the Nobel Prize in chemistry in 2004. Ubiquitin was first identified in 1975 as an 8.5 kDa protein of unknown function expressed in all eukaryotic cells, the ubiquitination system was initially characterised as an ATP-dependent proteolytic system present in cellular extracts. Multiple APF-1 molecules were linked to a substrate molecule by an isopeptide linkage. Soon after APF-1-protein conjugation was characterised, APF-1 was identified as ubiquitin, the carboxyl group of the C-terminal glycine residue of ubiquitin was identified as the moiety conjugated to substrate lysine residues. Ubiquitin is a protein that exists in all eukaryotic cells. It performs its functions through conjugation to a large range of target proteins. A variety of different modifications can occur, the ubiquitin protein itself consists of 76 amino acids and has a molecular mass of about 8.5 kDa. Key features include its C-terminal tail and the 7 lysine residues and it is highly conserved among eukaryotic species, Human and yeast ubiquitin share 96% sequence identity. Ubiquitin is encoded in mammals by 4 different genes, UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. The UBB and UBC genes code for polyubiquitin precursor proteins, no ubiquitin and ubiquitination machinery are known to exist in prokaryotes. However, ubiquitin is believed to have descended from prokaryotic proteins similar to ThiS or MoaD and these prokaryotic proteins, despite having little sequence identity, share the same protein fold. These proteins also share sulfur chemistry with ubiquitin, a similar system exists for ThiS, with its E1-like enzyme ThiF
17.
Proteasomes
–
Proteasomes are protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, proteasomes are located in the nucleus and the cytoplasm, the main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases, proteasomes are part of a major mechanism by which cells regulate the concentration of particular proteins and degrade misfolded proteins. The degradation process yields peptides of about seven to eight amino acids long, proteins are tagged for degradation with a small protein called ubiquitin. The tagging reaction is catalyzed by enzymes called ubiquitin ligases, once a protein is tagged with a single ubiquitin molecule, this is a signal to other ligases to attach additional ubiquitin molecules. The result is a chain that is bound by the proteasome. In structure, the proteasome is a complex containing a core of four stacked rings forming a central pore. Each ring is composed of seven individual proteins, the inner two rings are made of seven β subunits that contain three to seven protease active sites. These sites are located on the surface of the rings. The outer two rings each contain seven α subunits whose function is to maintain a gate through which proteins enter the barrel and these α subunits are controlled by binding to cap structures or regulatory particles that recognize polyubiquitin tags attached to protein substrates and initiate the degradation process. The overall system of ubiquitination and proteasomal degradation is known as the ubiquitin-proteasome system, the proteasomal degradation pathway is essential for many cellular processes, including the cell cycle, the regulation of gene expression, and responses to oxidative stress. However, work by Alfred Goldberg in 1977 on ATP-dependent protein degradation in reticulocytes and this was shown in 1978 to be composed of several distinct protein chains, a novelty among proteases at the time. It was then discovered that an identified protein associated with proteolytic degradation. The proteolytic activities of this system was isolated as a complex originally called the multi-catalytic proteinase complex by Sherwin Wilk. Later, the ATP-dependent proteolytic complex that was responsible for ubiquitin-dependent protein degradation was discovered and was called the 26S proteasome, hershkos year-long sabbatical in the laboratory of Irwin Rose at the Fox Chase Cancer Center provided key conceptual insights, though Rose later downplayed his role in the discovery. The three shared the 2004 Nobel Prize in Chemistry for their work in discovering this system, the proteasome subcomponents are often referred to by their Svedberg sedimentation coefficient. The core is hollow and provides a cavity in which proteins are degraded. The inner two rings each consist of seven β subunits and contain the active sites that perform the proteolysis reactions
18.
Interphase
–
Interphase is the phase of the cell cycle in which a typical cell spends most of its life. During this phase, the cell copies its DNA in preparation for mitosis, interphase is the daily living or metabolic phase of the cell, in which the cell obtains nutrients and metabolizes them, grows, reads its DNA, and conducts other normal cell functions. The majority of eukaryotic cells spend most of their time in interphase and this phase was formerly called the resting phase. However, interphase does not describe a cell that is resting, rather, the cell is actively living. A common misconception is that interphase is the first stage of mitosis, however, since mitosis is the division of the nucleus, prophase is actually the first stage. In interphase, the cell gets itself ready for mitosis or meiosis, there are three stages of cellular interphase, with each phase ending when a cellular checkpoint checks the accuracy of the stages completion before proceeding to the next. The stages of interphase are, G1, in which the cell grows, during this time, a high amount of protein synthesis occurs and the cell grows - more organelles are produced and the volume of the cytoplasm increases. If the cell is not to again, it will enter G0. Synthesis, in which the cell duplicates its DNA, G2, in which the cell resumes its growth in preparation for division. The mitochondria divide and the continues to grow until mitosis begins. In plants, chloroplasts also divide during G2, in addition, some cells that do not divide often or ever, enter a stage called G0, which is either a stage separate from interphase or an extended G1. The duration of time spent in interphase and in stage of interphase is variable. Most cells of adult mammals spend about 20 hours in interphase, interphase includes G1, S, and G2 phases. Mitosis and cytokinesis, however, are separate from interphase, when G2 is completed, the cell enters a relatively brief period of nuclear and cellular division, composed of mitosis and cytokinesis, respectively. After the successful completion of mitosis and cytokinesis, both resulting daughter cells re-enter G1 of interphase, in the cell cycle, interphase is preceded by telophase and cytokinesis of the M phase. In alternative fashion, interphase is sometimes interrupted by G0 phase, after the successful completion of the G2 checkpoint, the final checkpoint in interphase, the cell proceeds to prophase, or in plants to preprophase, which is the first stage of mitosis. G0 phase is viewed as either an extended G1 phase where the cell is neither dividing nor preparing to divide, in gamete production interphase is succeeded by meiosis. In programmed cell death, interphase is followed or preempted by apoptosis
19.
Prophase
–
Prophase, is a stage of Mitosis. This is when the chromatin condenses into two rod-shaped structures called chromosomes in which the chromatin becomes visible and this process, known as chromatin condensation, is involved with the condensin complex. Since the genetic material has been replicated in the interphase of the cell cycle. Those copies are called sister chromatids and they are attached to each other at a DNA element present on every chromosome called the centromere, also during prophase, giemsa staining can be applied to elicit G-banding in chromosomes. An important organelle in mitosis is the centrosome, the organizing center in metazoans. During prophase, the two centrosomes, which replicate independently of mitosis, have their microtubule-activity increased due to the recruitment of γ-tubulin, the centrosomes will be pushed apart to opposite ends of the cell nucleus by the action of molecular motors acting on the microtubules. At the end of prophase, the tiny nucleolus within the nucleus dissolves, the nucleolus starts moving towards the nuclear membrane at the beginning of prophase, and its disintegration occurs near the nuclear envelope. Its contents are dispersed in masses, basically, the chromatin in the nucleus coils into chromosomes. The centrosomes move to opposite poles of the cell, forming a bridge of spindle fibers, at the end of prophase, the nucleolus disperses. In prometaphase, the step of mitosis, the nuclear membrane breaks apart. Interphase Metaphase Anaphase Telophase Farhan Phase Media related to Prophase at Wikimedia Commons
20.
Prometaphase
–
Prometaphase is the phase of mitosis following prophase and preceding metaphase, in eukaryotic somatic cells. Prometaphase is sometimes included as part of the end of prophase. In prometaphase, the nuclear membrane breaks apart into numerous membrane vesicles, kinetochore microtubules emerging from the centrosomes at the poles of the spindle reach the chromosomes and attach to the kinetochores, throwing the chromosomes into agitated motion. Other spindle microtubules make contact with microtubules coming from the opposite pole, forces exerted by protein motors associated with spindle microtubules move the chromosomes toward the center of the cell. The microtubules are composed of two types, kinetochore microtubules and non-kinetochore microtubules, kinetochore microtubules begin searching for kinetochores to attach to. A number of microtubules or polar microtubules find and interact with corresponding nonkinetochore microtubules from the opposite centrosome to form the mitotic spindle. The role of prometaphase is completed all of the kinetochore microtubules have attached to their kinetochores. An unattached kinetochore, and thus a non-aligned chromosome, even when most of the chromosomes have lined up. This prevents premature progression into anaphase by inhibiting the complex until all kinetochores are attached. Media related to Prometaphase at Wikimedia Commons
21.
Meiosis
–
This process occurs in all sexually reproducing single-celled and multicellular eukaryotes, including animals, plants, and fungi. Errors in meiosis resulting in aneuploidy are the known cause of miscarriage. In meiosis, DNA replication is followed by two rounds of division to produce four potential daughter cells, each with half the number of chromosomes as the original parent cell. The two meiotic divisions are known as Meiosis I and Meiosis II and this S-phase can be referred to as premeiotic S-phase or meiotic S-phase. Immediately following DNA replication, meiotic cells enter a prolonged G2-like stage known as meiotic prophase, a subset of recombination events results in crossovers, which create physical links known as chiasmata between the homologous chromosomes. During Meiosis II, the cohesion between sister chromatids is released and they segregate from one another, as during mitosis, in some cases all four of the meiotic products form gametes such as sperm, spores, or pollen. In female animals, three of the four meiotic products are eliminated by extrusion into polar bodies, and only one cell develops to produce an ovum. Because the number of chromosomes is halved during meiosis, gametes can fuse to form a zygote that contains two copies of each chromosome, one from each parent. Thus, alternating cycles of meiosis and fertilization enable sexual reproduction, for example, diploid human cells contain 23 pairs of chromosomes including 1 pair of sex chromosomes, half of maternal origin and half of paternal origin. Meiosis produces haploid gametes that contain one set of 23 chromosomes, when two gametes fuse, the resulting zygote is once again diploid, with the mother and father each contributing 23 chromosomes. This same pattern, but not the number of chromosomes. First, the cell undergoes DNA replication, so each homolog now consists of two sister chromatids. Then each set of homologs pair with other and exchange DNA by homologous recombination leading to physical connections between the homologs. In the first meiotic division, the homologs are segregated to daughter cells by the spindle apparatus. The cells then proceed to a division without an intervening round of DNA replication. The sister chromatids are segregated to daughter cells to produce a total of four haploid cells. Female animals employ a variation on this pattern and produce one large ovum. Because of recombination, an individual chromatid can consist of a new combination of maternal and paternal DNA, furthermore, an individual gamete can include an assortment of maternal, paternal, and recombinant chromatids
22.
Cdc20
–
The cell-division cycle protein 20 is an essential regulator of cell division that is encoded by the CDC20 gene in humans. The APC/CCdc20 protein complex has two main downstream targets, firstly, it targets securin for destruction, enabling the eventual destruction of cohesin and thus sister chromatid separation. It also targets S and M-phase cyclins for destruction, which inactivates S/M cyclin-dependent kinases, a closely related protein, Cdc20homologue-1 plays a complementary role in the cell cycle. CDC20 appears to act as a regulatory protein interacting with other proteins at multiple points in the cell cycle. It is required for two microtubule-dependent processes, nuclear movement prior to anaphase, and chromosome separation, hartwell found mutants that did not enter anaphase and thus could not complete mitosis, this phenotype could be traced back to the CDC20 gene. However, even after the biochemistry of the protein was eventually elucidated, Cdc20 is a protein related to the beta subunit of heterotrimeric G proteins. Near its C-terminus it contains seven WD40 repeats, which are multiple short, in the case of Cdc20, they arrange into a seven-bladed beta propeller. The human Cdc20 is about 499 amino acids long, and contains at least four phosphorylation sites near the N-terminus, in between these phosphorylation sites, which play regulatory roles, are the C-box, the KEN-box, the Mad2-interacting motif, and the Cry box. The KEN-box, as well as the Cry box, are important recognition and degradation sequences for the APC/CCdh1 complex, CDC20 has been shown to interact with, ANAPC7 BUB1B, CDC16, CDC27, Cyclin A1, FBXO5, HDAC1, HDAC2, and MAD2L1. However, the most important interaction of Cdc20 is with the Anaphase Promoting Complex, the APC/C is a large E3 ubiquitin ligase, which triggers the metaphase to anaphase transition by marking select proteins for degradation. The two main targets of the APC/C are the S/M cyclins and the protein securin, S/M cyclins activate cyclin-dependent kinases, which have a vast array of downstream effects that work to guide the cell through mitosis. They must be degraded for cells to exit mitosis, securin is a protein that activates separase, which in turn inhibits cohesin, a protein that holds sister chromatids together. Therefore, in order for anaphase to progress, securin must be inhibited so that cohesin can be cleaved by separase. These processes are dependent on both the APC/C and Cdc20, When Cdks phosphorylate the APC/C, Cdc20 can bind and activate it, APC/C activity is dependent on Cdc20, because Cdc20 often binds the APC/C substrates directly. In fact, it is thought that Cdc20 and Cdh1 are receptors for the KEN-box and D-box motifs on substrates, however, these sequences are normally not sufficient for ubiquitination and degradation, much remains to be learned about how Cdc20 binds its substrate. The APC/CCdc20 complex regulates itself so that it is present during the times of the cell cycle. In order for Cdc20 to bind the APC/C, specific APC/C subunits must be phosphorylated by Cdk1, therefore, when cdk activity is high in mitosis, and the cell must prepare to enter anaphase and exit mitosis, the APC/CCdc20 complex is activated. Once active, APC/CCdc20 promotes the degradation of Cdks by inactivating S/M cyclins, Cdk degradation brings about lower rates of APC/C phosphorylation and thus lower rates of Cdc20 binding
23.
PubMed Identifier
–
PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. The United States National Library of Medicine at the National Institutes of Health maintains the database as part of the Entrez system of information retrieval, from 1971 to 1997, MEDLINE online access to the MEDLARS Online computerized database primarily had been through institutional facilities, such as university libraries. PubMed, first released in January 1996, ushered in the era of private, free, home-, the PubMed system was offered free to the public in June 1997, when MEDLINE searches via the Web were demonstrated, in a ceremony, by Vice President Al Gore. Information about the journals indexed in MEDLINE, and available through PubMed, is found in the NLM Catalog. As of 5 January 2017, PubMed has more than 26.8 million records going back to 1966, selectively to the year 1865, and very selectively to 1809, about 500,000 new records are added each year. As of the date,13.1 million of PubMeds records are listed with their abstracts. In 2016, NLM changed the system so that publishers will be able to directly correct typos. Simple searches on PubMed can be carried out by entering key aspects of a subject into PubMeds search window, when a journal article is indexed, numerous article parameters are extracted and stored as structured information. Such parameters are, Article Type, Secondary identifiers, Language, publication type parameter enables many special features. As these clinical girish can generate small sets of robust studies with considerable precision, since July 2005, the MEDLINE article indexing process extracts important identifiers from the article abstract and puts those in a field called Secondary Identifier. The secondary identifier field is to store numbers to various databases of molecular sequence data, gene expression or chemical compounds. For clinical trials, PubMed extracts trial IDs for the two largest trial registries, ClinicalTrials. gov and the International Standard Randomized Controlled Trial Number Register, a reference which is judged particularly relevant can be marked and related articles can be identified. If relevant, several studies can be selected and related articles to all of them can be generated using the Find related data option, the related articles are then listed in order of relatedness. To create these lists of related articles, PubMed compares words from the title and abstract of each citation, as well as the MeSH headings assigned, using a powerful word-weighted algorithm. The related articles function has been judged to be so precise that some researchers suggest it can be used instead of a full search, a strong feature of PubMed is its ability to automatically link to MeSH terms and subheadings. Examples would be, bad breath links to halitosis, heart attack to myocardial infarction, where appropriate, these MeSH terms are automatically expanded, that is, include more specific terms. Terms like nursing are automatically linked to Nursing or Nursing and this important feature makes PubMed searches automatically more sensitive and avoids false-negative hits by compensating for the diversity of medical terminology. The My NCBI area can be accessed from any computer with web-access, an earlier version of My NCBI was called PubMed Cubby
24.
Protein
–
Proteins are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, a linear chain of amino acid residues is called a polypeptide. A protein contains at least one long polypeptide, short polypeptides, containing less than 20–30 residues, are rarely considered to be proteins and are commonly called peptides, or sometimes oligopeptides. The individual amino acid residues are bonded together by peptide bonds, the sequence of amino acid residues in a protein is defined by the sequence of a gene, which is encoded in the genetic code. In general, the code specifies 20 standard amino acids, however. Sometimes proteins have non-peptide groups attached, which can be called prosthetic groups or cofactors, proteins can also work together to achieve a particular function, and they often associate to form stable protein complexes. Once formed, proteins only exist for a period of time and are then degraded and recycled by the cells machinery through the process of protein turnover. A proteins lifespan is measured in terms of its half-life and covers a wide range and they can exist for minutes or years with an average lifespan of 1–2 days in mammalian cells. Abnormal and or misfolded proteins are degraded more rapidly due to being targeted for destruction or due to being unstable. Like other biological macromolecules such as polysaccharides and nucleic acids, proteins are essential parts of organisms, many proteins are enzymes that catalyse biochemical reactions and are vital to metabolism. Proteins also have structural or mechanical functions, such as actin and myosin in muscle and the proteins in the cytoskeleton, other proteins are important in cell signaling, immune responses, cell adhesion, and the cell cycle. In animals, proteins are needed in the diet to provide the essential amino acids that cannot be synthesized, digestion breaks the proteins down for use in the metabolism. Methods commonly used to study structure and function include immunohistochemistry, site-directed mutagenesis, X-ray crystallography, nuclear magnetic resonance. Most proteins consist of linear polymers built from series of up to 20 different L-α-amino acids, all proteinogenic amino acids possess common structural features, including an α-carbon to which an amino group, a carboxyl group, and a variable side chain are bonded. Only proline differs from this structure as it contains an unusual ring to the N-end amine group. The amino acids in a chain are linked by peptide bonds. Once linked in the chain, an individual amino acid is called a residue, and the linked series of carbon, nitrogen. The peptide bond has two forms that contribute some double-bond character and inhibit rotation around its axis, so that the alpha carbons are roughly coplanar
25.
Cyclin A
–
Cyclin A is a member of the cyclin family, a group of proteins that function in regulating progression through the cell cycle. One such regulatory component is cyclin A which plays a role in the regulation of two different cell cycle stages, Cyclin A was first identified in 1983 in sea urchin embryos. The protein exists in both a form and somatic form. A single cyclin A gene has been identified in Drosophila while Xenopus, mice, Cyclin A1 is prevalently expressed during meiosis and early on in embryogenesis. Cyclin A2 is expressed in dividing somatic cells, the interaction between the cyclin box, a region conserved across cyclins, and a region of the CDK, called the PSTAIRE, confers the foundation of the cyclin-CDK complex. Cyclin A is the only cyclin that regulates multiple steps of the cell cycle, Cyclin A can regulate multiple cell cycle steps because it associates with, and thereby activates, two distinct CDKs- CDK2 and CDK1. Depending on which CDK partner cyclin A binds, the cell will continue through the S phase or it will transition from G2 to the M phase. Association of cyclin A with CDK2 is required for passage into S phase while association with CDK1 is required for entry into M phase, Cyclin A resides in the nucleus during S phase where it is involved in the initiation and completion of DNA replication. As the cell passes from G1 into S phase, cyclin A associates with CDK2 and this complex makes chromatin capable of replication. When the amount of cyclin A/CDK2 complex reaches a threshold level, as the amount of Cyclin A/CDK2 complex increases, the complex initiates DNA replication. This is thought to occur through the phosphorylation of particular DNA replication machinery components, such as CDC6, by the cyclin A/CDK2 complex. Since the action of cyclin A/CDK2 inhibits that of cyclin E/CDK2, in late S phase, cyclin A can also associate with CDK1. Cyclin A remains associated with CDK1 from late S into late G2 phase when it is replaced by cyclin B, Cyclin A/CDK1 is thought to be involved in the activation and stabilization of cyclin B/CDK1 complex. Once cyclin B is activated, cyclin A is no longer needed and is degraded through the ubiquitin pathway. Degradation of cyclin A/CDK1 induces mitotic exit, Cyclin A/CDK2 complex was thought to be restricted to the nucleus and thus exclusively involved in S phase progression. New research has since debunked this assumption, shedding light on cyclin A/CDK2 migration to the centrosomes in late G2, Cyclin A binds to the mitotic spindle poles in the centrosome however, the mechanism by which the complex is shuttled to the centrosome is not well understood. It is suspected that the presence of cyclin A/CDK2 at the centrosomes may confer a means of regulating the movement of cyclin B/CDK1 to the centrosome, a study in 2008 provided further evidence of cyclin A/CDK2 complex’s role in mitosis. Cells were modified so their CDK2 was inhibited and their cyclin A2 gene was knocked out and these mutants entered mitosis late due to a delayed activation of the cyclin B/CDK1 complex
26.
Cyclin A1
–
Cyclin-A1 is a protein that in humans is encoded by the CCNA1 gene. The protein encoded by this gene belongs to the conserved cyclin family. Cyclins function as activating subunits of enzymatic complex together with cyclin-dependent kinases, different cyclins exhibit distinct expression and degradation patterns that contribute to the temporal coordination of cell cycle events. Cyclin A1 was shown to be expressed in testis and brain, as well as in several leukemic cell lines, and is thought to primarily function in the control of meiosis. This cyclin binds both Cdk1 and Cdk2 kinases, which two distinct kinase activities, one appearing in S phase, the other in G2. This cyclin was found to bind to important cell cycle regulators, such as Rb family proteins, transcription factor E2F1, and the Kip/Cip family of CDK-inhibitor proteins
27.
Cyclin A2
–
Cyclin-A2 is a protein that in humans is encoded by the CCNA2 gene. It is one of the two types of cyclin A, cyclin A1 is expressed during meiosis and embryogenesis while cyclin A2 is expressed in dividing somatic cells, cyclin A2 belongs to the cyclin family, whose members regulate cell cycle progression by interacting with CDK kinases. Cyclin A2 is unique in that it can activate two different CDK kinases, it binds CDK2 during S phase, and CDK1 during the transition from G2 to M phase. Cyclin A2 is synthesized at the onset of S phase and localizes to the nucleus, phosphorylation of CDC6 and MCM4 by the cyclin A2-CDK2 complex prevents re-replication of DNA during the cell cycle. Cyclin A2 is involved in the G2/M transition but it cannot independently form a maturation promoting factor, recent studies have shown that the cyclin A2-CDK1 complex triggers cyclin B1-CDK1 activation which results in chromatin condensation and the breakdown of the nuclear envelope. The levels of cyclin A2 are tightly synchronized with the progression of the cell cycle, transcription initiates in late G1, peaks and plateaus in mid-S, and declines in G2. Cyclin A2 transcription is regulated by the transcription factor E2F and begins in G1. Absence of cyclin A2 before the R point is due to the E2F inhibition by hypophosphorylated retinoblastoma protein, after the R point, pRb is phosphorylated and can no longer bind E2F, leading to cyclin A2 transcription. The cyclin A2-CDK2 complex eventually phosphorylates E2F, turning off cyclin A2 transcription, E2F promotes cyclin A2 transcription by de-repressing the promoter. Cyclin A2 has been shown to interact with, CDC6, E2F1, FEN1, ITGB3BP, RBL1, cyclin A2 is a key protein involved in the direction of mammalian cardiac myocytes to grow and divide, and has been shown to induce cardiac repair following myocardial infarction. Normally, Ccna2 is silenced postnatally in mammalian cardiac myocytes, because of this gene silencing, adult heart muscle cells cannot divide readily to repair and regenerate after a heart attack. Ccna2 has been found to induce cardiac repair in small-animal models following myocardial infarction, preclinical trials involving injections of adenovirus which contained the Ccna2 gene into infarcted porcine hearts has shown to be protective of MI in pig hearts. Ccna2 mediated cardiac repair showed both a decrease in fibrosis in the tissue and a greater number of cardiomyocytes at the sites of injection. Delivery of Ccna2 into cardiac tissue invokes a response and markedly enhances cardiac function. Increased expression of cyclin A2 has been observed in many types of such as breast, cervical, liver. While it is not clear whether increased expression of cyclin A2 is a cause or result of tumorigenesis, overexpression of cyclin A2 in mammalian cells can result in the delayed onset of metaphase and anaphase. It is also possible that cyclin A2-CDK contributes to tumorigenesis by the phosphorylation of oncoproteins or tumor suppressors like p53
28.
Cyclin B
–
Cyclin B is a member of the cyclin family. Cyclin B is a mitotic cyclin, the amount of cyclin B and the activity of the cyclin B-Cdk complex rise through the cell cycle until mitosis, where they fall abruptly due to degradation of cyclin B. The complex of Cdk and cyclin B is called maturation promoting factor or mitosis promoting factor, Cyclin B is necessary for the progression of the cells into and out of M phase of the cell cycle. At the end of S phase the phosphatase cdc25c dephosphorylates tyrosine15, upon activation the complex is shuttled to the nucleus where it serves to trigger for entry into mitosis. However, if DNA damage is detected alternative proteins are activated which results in the phosphorylation of cdc25c. In order for the cell to progress out of mitosis, the degradation of cyclin B is necessary, the cyclin B/CDK1 complex also interacts with a variety of other key proteins and pathways which regulate cell growth and progression of mitosis. Cross-talk between many of these pathways links cyclin B levels indirectly to induction of apoptosis, the cyclin B/CDK1 complex plays a critical role in the expression of the survival signal survivin. Survivin is necessary for proper creation of the spindle which strongly affects cell viability. A decrease in levels and the associated mitotic disarray triggers apoptosis via caspase 3 mediated pathway. Cyclin B plays in role in many types of cancer. Hyperplasia is one of the hallmarks of cancer, because cyclin B is necessary for cells to enter mitosis and therefore necessary for cell division, cyclin B levels are often de-regulated in tumors. When cyclin B levels are elevated, cells can enter M phase prematurely and strict control over cell division is lost, on the other hand, if cyclin B levels are depleted the cyclin B/CDK1 complex cannot form, cells cannot enter M phase and cell division slows down. Some anti-cancer therapies have been designed to prevent cyclin B/CDK1 complex formation in cancer cells to slow or prevent cell division, most of these methods have targeted the CDK1 subunit, but there is an emerging interest in the oncology field to target cyclin B as well. Cyclin levels can easily be determined through analysis of tumor biopsies. The fact that cyclin B is often disregulated in cancer cells makes cyclin B an attractive biomarker, many studies have been performed to examine cyclin levels in tumors, and it has been shown that levels of cyclin B is a strong indicator of prognosis in many types of cancer. Generally, elevated levels of cyclin B are indicative of more aggressive cancers, immunohistologically assessed levels of cyclin B could determine if women with stage 1, node negative, hormone receptor positive breast cancer were likely to benefit from adjuvant therapy. In general women with this cancer have a good prognosis. Therefore, it is rare for oncologists to recommend adjuvant chemotherapy in these cases, however, in a small subset of patient this type of cancer is unexpectedly aggressive
29.
Cyclin B1
–
G2/mitotic-specific cyclin-B1 is a protein that in humans is encoded by the CCNB1 gene. Cyclin B1 is a protein involved in mitosis. The gene product complexes with p34 to form the maturation-promoting factor, two alternative transcripts have been found, a constitutively expressed transcript and a cell cycle-regulated transcript that is expressed predominantly during G2/M phase of the cell cycle. The different transcripts result from the use of transcription initiation sites. Cyclin B1 contributes to the all or none behavior of the cell in deciding to commit to mitosis. Its activation is well-regulated, and positive feedback loops ensure that once the cyclin B1-Cdk1 complex is activated, cyclin B1-Cdk1 is involved in the early events of mitosis, such as chromosome condensation, nuclear envelope breakdown, and spindle pole assembly. Once activated, cyclin B1-Cdk1 promotes several of the events of early mitosis, the active complex phosphorylates and activates 13S condensin, which helps to condense chromosomes. Another important function of the cyclin B1-Cdk1 complex is to break down the nuclear envelope, the nuclear envelope is a membranous structure containing large protein complexes supported by a network of nuclear lamins. Phosphorylation of the lamins by cyclin B1-Cdk1 causes them to dissociate, the destruction of the nuclear envelope is important because it allows the mitotic spindle to access the chromosomes. Like all cyclins, levels of cyclin B1 oscillate over the course of the cell cycle, just prior to mitosis, a large amount of cyclin B1 is present in the cell, but it is inactive due to phosphorylation of Cdk1 by the Wee1 kinase. The complex is activated by dephosphorylation by the phosphatase Cdc25, Cdc25 is always present in the cell but must be activated by phosphorylation. A possible trigger for activation is phosphorylation by cyclin A-Cdk, which functions before cyclin B1-Cdk in the cell cycle, active Cdk1 is also capable of phosphorylating and activating Cdc25 and thus promote its own activation, resulting in a positive feedback loop. Once cyclin B1-Cdk1 is activated, it remains active for the rest of mitosis. Another mechanism by which cyclin B1-Cdk1 activity is regulated is through subcellular localization, before mitosis almost all cyclin B1 in the cell is located in the cytoplasm, but in late prophase it relocates to the nucleus. This is regulated by the phosphorylation of cyclin B1, in contrast to phosphorylation of Cdk1 regulating the activity of the complex, phosphorylation of cyclin B1 causes it to be imported to the nucleus, and phosphorylation also prevents export from the nucleus by blocking the nuclear export signal. Cyclin B1 is phosphorylated by Polo kinase and Cdk1, again setting up a feedback loop that commits cyclin B1-Cdk1 to its fate. At the end of mitosis, cyclin B1 is targeted for degradation by the APC through its APC localization sequence, cyclin B1 has been shown to interact with Cdk1, GADD45A and RALBP1. One of the hallmarks of cancer is the lack of regulation in the cell cycle, binding of Cdks can lead to phosphorylation of other substrates at inappropriate time and unregulated proliferation
30.
Cyclin B2
–
G2/mitotic-specific cyclin-B2 is a protein that in humans is encoded by the CCNB2 gene. Cyclin B2 is a member of the family, specifically the B-type cyclins. The B-type cyclins, B1 and B2, associate with p34cdc2 and are components of the cell cycle regulatory machinery. B1 and B2 differ in their subcellular localization, cyclin B1 co-localizes with microtubules, whereas cyclin B2 is primarily associated with the Golgi region. Cyclin B2 also binds to transforming growth factor beta RII and thus cyclin B2/cdc2 may play a key role in transforming growth factor beta-mediated cell cycle control, cyclin B2 has been shown to interact with TGF beta receptor 2
31.
Cyclin D
–
Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition, Cyclin D protein is anywhere from 155 to 477 amino acids in length. Once the cells reach a cell size and if growth factors and mitogens or nutrients are present. In general, all stages of the cycle are chronologically separated in humans and are triggered by cyclin-Cdk complexes which are periodically expressed. Cyclins are eukaryotic proteins that form holoenzymes with cyclin-dependent protein kinases, the abundance of cyclins is generally regulated by protein synthesis and degradation through an APC/C dependent pathway. Cyclin D is one of the major cyclins produced in terms of its functional importance and it interacts with four Cdks, Cdk2,4,5, and 6. In proliferating cells, cyclin D-Cdk4/6 complex accumulation is of importance for cell cycle progression. Namely, cyclin D-Cdk4/6 complex partially phosphorylates retinoblastoma tumor suppressor protein, mice, Drosophila and many other organisms only have one cyclin D protein. In humans, in addition to the mouse homologue, two more cyclin D proteins have been identified and these human proteins, called cyclin D1, cyclin D2, and cyclin D3 are expressed in most proliferating cells and the relative amounts expressed differ in various cell types. The most studied homologues of cyclin D are found in yeast, the yeast homologue of cyclin D, referred to as Cln3, interacts with Cdc28 during G1. In viruses, like Saimiriine herpesvirus 2 and Human herpesvirus 8 cyclin D homologues have acquired new functions in order to manipulate the host cell’s metabolism to the viruses’ benefit, other than Rb, viral cyclin D-Cdk6 complex also targets p27Kip, a Cdk inhibitor of cyclin E and A. In addition, viral cyclin D-Cdk6 is resistant to Cdk inhibitors, such as p21CIP1/WAF1, growth factors stimulate the Ras/Raf/ERK that induce cyclin D production. One of the members of the pathways, MAPK activates a transcription factor Myc, in this way, cyclin D is synthesized as long as the growth factor is present. Even though cyclin D levels in proliferating cells are sustained as long as the factors are present. Despite this, cyclin D has no effect on G1/S transition unless it forms a complex with Cdk 4 or 6, one of the best known substrates of cyclin D/Cdk4 and -6 is the retinoblastoma tumor suppressor protein. Rb is an important regulator of genes responsible for progression through the cell cycle, in its un-phosphorylated form, Rb binds a member of E2F family of transcription factors which controls expression of several genes involved in cell cycle progression. Rb acts as a repressor, so in complex with E2F it prevents expression of E2F-regulated genes, subsequently, cyclin E/Cdk2 fully phosphorylates Rb and completes its inactivation. Cyclin D is regulated by the pathway of mitogen receptors via the Ras/MAP kinase
32.
Cyclin D1
–
Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase enzymes. Cyclins were originally discovered by R. Timothy Hunt in 1982 while studying the cell cycle of sea urchins, in an interview for The Life Scientific hosted by Jim Al-Khalili, R. Timothy Hunt explained that the name cyclin was originally named after his hobby cycling. It was only after the naming did its importance in the cell cycle become apparent, as it was appropriate the name stuck. R. Timothy Hunt, By the way, the cyclin, which I coined, was really a joke, its because I liked cycling so much at the time. Cyclins were originally named because their concentration varies in a fashion during the cell cycle. A cyclin forms a complex with Cdk, which begins to activate the Cdk, complex formation results in activation of the Cdk active site. Cyclins themselves have no enzymatic activity but have binding sites for some substrates, Cyclins, when bound with the dependent kinases, such as the p34/cdc2/cdk1 protein, form the maturation-promoting factor. MPFs activate other proteins through phosphorylation and these phosphorylated proteins, in turn, are responsible for specific events during cycle division such as microtubule formation and chromatin remodeling. Cyclins can be divided into four classes based on their behavior in the cycle of vertebrate somatic cells and yeast cells, G1 cyclins, G1/S cyclins, S cyclins. This division is useful when talking about most cell cycles, G1/S Cyclins rise in late G1 and fall in early S phase. The Cdk- G1/S cyclin complex begins to induce the initial processes of DNA replication, the cyclins also promote other activities to progress the cell cycle, such as centrosome duplication in vertebrates or spindle pole body in yeast. The rise in presence of G1/S cyclins is paralleled by a rise in S cyclins, G1 cyclins do not behave like the other cyclins, in that the concentrations increase gradually, throughout the cell cycle based on cell growth and the external growth-regulatory signals. The presence of G cyclins coordinate cell growth with the entry to a new cell cycle, S cyclins bind to Cdk and the complex directly induces DNA replication. The levels of S cyclins remain high, not only throughout S phase, M cyclin concentrations rise as the cell begins to enter mitosis and the concentrations peak at metaphase. Cell changes in the cell cycle like the assembly of mitotic spindles, the destruction of M cyclins during metaphase and anaphase, after the Spindle Assembly Checkpoint is satisfied, causes the exit of mitosis and cytokinesis. Cyclins are generally different from each other in primary structure. However, all members of the family are similar in 100 amino acids that make up the cyclin box. Cyclins contain two domains of a similar fold, the first located at the N-terminus and the second at the C-terminus
33.
Cyclin D2
–
G1/S-specific cyclin-D2 is a protein that in humans is encoded by the CCND2 gene. The protein encoded by this gene belongs to the conserved cyclin family. Cyclins function as regulators of cyclin-dependent kinases, different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a subunit of CDK4 or CDK6. This protein has shown to interact with and be involved in the phosphorylation of tumor suppressor protein Rb. Knockout studies of the gene in mouse suggest the essential roles of this gene in ovarian granulosa. High level expression of this gene was observed in ovarian and testicular tumors, mutations in CCND2 are associated to megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome
34.
Cyclin D3
–
G1/S-specific cyclin-D3 is a protein that in humans is encoded by the CCND3 gene. The protein encoded by this gene belongs to the conserved cyclin family. Cyclins function as regulators of CDK kinases, different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a subunit of CDK4 or CDK6. This protein has shown to interact with and be involved in the phosphorylation of tumor suppressor protein Rb. The CDK4 activity associated with this cyclin was reported to be necessary for cell cycle progression through G2 phase into mitosis after UV radiation, mutations in CCND3 are implicated in cases of breast cancer. Cyclin D3 has been shown to interact with, Cyclin Cyclin D
35.
Cyclin E
–
Cyclin E is a member of the cyclin family. Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase of the cycle that determines initiation of DNA duplication. The Cyclin E/CDK2 complex phosphorylates p27Kip1, tagging it for degradation, thus promoting expression of Cyclin A, like all cyclin family members, cyclin E forms a complex with cyclin-dependent kinase. Cyclin E/CDK2 regulates multiple cellular processes by phosphorylating numerous downstream proteins, Cyclin E/CDK2 plays a critical role in the G1 phase and in the G1-S phase transition. Cyclin E/CDK2 phosphorylates retinoblastoma protein to promote G1 progression, hyper-phosphorylated Rb will no longer interact with E2F transcriptional factor, thus release it to promote expression of genes that drive cells to S phase through G1 phase. Cyclin E/CDK2 also phosphorylates p27 and p21 during G1 and S phases, Smad3, a key mediator of TGF-β pathway which inhibits cell cycle progression, can be phosphorylated by cyclin E/CDK2. The phosphorylation of Smad3 by cyclin E/CDK2 inhibits its transcriptional activity, cBP/p300 and E2F-5 are also substrates of cyclin E/CDK2. Phosphorylation of these two proteins stimulates the transcriptional events during cell cycle progression, Cyclin E/CDK2 can phosphorylate p220 to promote histone gene transcription during cell cycle progression. Apart from the function in cell cycle progression, cyclin E/CDK2 plays a role in the centrosome cycle and this function is performed by phosphorylating nucleophosmin. Then NPM is released from binding to an unduplicated centrosome, thereby triggering duplication, cP110 is another cyclin E/CDK2 substrate which involves in centriole duplication and centrosome separation. Cyclin E/CDK2 has also shown to regulate the apoptotic response to DNA damage via phosphorylation of FOXO1. Over-expression of cyclin E correlates with tumorigenesis and it is involved in various types of cancers, including breast, colon, bladder, skin and lung cancer. DNA copy-number amplification of cyclin E1 is involved in brain cancer, besides that, dysregulated cyclin E activity causes cell lineage-specific abnormalities, such as impaired maturation due to increased cell proliferation and apoptosis or senescence. Several mechanisms lead to the expression of cyclin E. In most cases, gene amplification causes the overexpression, proteosome caused defected degradation is another mechanism. Loss-of-function mutations of FBXW7 were found in cancer cells. FBXW7 encodes F-box proteins which target cyclin E for ubiquitination, Cyclin E overexpression can lead to G1 shortening, decrease in cell size or loss of serum requirement for proliferation. Dysregulation of cyclin E occurs in 18-22% of the breast cancers, Cyclin E is a prognostic marker in breast cancer, its altered expression increased with the increasing stage and grade of the tumor
36.
Cyclin E1
–
G1/S-specific cyclin-E1 is a protein that in humans is encoded by the CCNE1 gene. The protein encoded by this gene belongs to the conserved cyclin family. Cyclins function as regulators of CDK, different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a subunit of CDK2. This protein accumulates at the G1-S phase boundary and is degraded as cells progress through S phase, overexpression of this gene has been observed in many tumors, which results in chromosome instability, and thus may contribute to tumorigenesis. Two alternatively spliced variants of this gene, which encode distinct isoforms, have been described. Two additional splice variants were reported but detailed nucleotide sequence information is not yet available, cyclin E1 has been shown to interact with, cyclin E
37.
Cyclin-dependent kinase
–
Cyclin-dependent kinases are a family of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and they are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved. In fact, yeast cells can proliferate normally when their CDK gene has been replaced with the human gene. CDKs are relatively small proteins, with weights ranging from 34 to 40 kDa. By definition, a CDK binds a protein called a cyclin. Without cyclin, CDK has little activity, only the cyclin-CDK complex is an active kinase. CDKs phosphorylate their substrates on serines and threonines, so they are serine-threonine kinases, Table 1, Known CDKs, their cyclin partners, and their functions in the human and consequences of deletion in mice. Most of the known cyclin-CDK complexes regulate the progression through the cell cycle, animal cells contain at least nine CDKs, four of which, CDK1,2,3, and 4, are directly involved in cell cycle regulation. In mammalian cells, CDK1, with its partners cyclin A2 and B1, another one, CDK7, is involved indirectly as the CDK-activating kinase. Cyclin-CDK complexes phosphorylate substrates appropriate for the cell cycle phase. Cyclin-CDK complexes of earlier cell-cycle phase help activate cyclin-CDK complexes in later phase, Table 2, Cyclins and CDKs by Cell-Cycle Phase Table 3, Cyclin-dependent kinases that control the cell cycle in model organisms. A list of CDKs with their regulator protein, cyclin or other, CDK1, cyclin A, cyclin B CDK2, cyclin A, cyclin E CDK3, cyclin C CDK4, cyclin D1, cyclin D2, cyclin D3 CDK5, CDK5R1, CDK5R2. Most knowledge of CDK structure and function is based on CDKs of S. pombe, S. cerevisiae, the four major mechanisms of CDK regulation are cyclin binding, CAK phosphorylation, regulatory inhibitory phosphorylation, and binding of CDK inhibitory subunits. The active site, or ATP-binding site, of all kinases is a cleft between a small amino-terminal lobe and a larger carboxy-terminal lobe, the structure of human Cdk2 revealed that CDKs have a modified ATP-binding site that can be regulated by cyclin binding. Phosphorylation by CDK-activating kinase at Thr 161 on the T-loop increases the complex activity, without cyclin, a flexible loop called the activation loop or T-loop blocks the cleft, and the position of several key amino acid residues is not optimal for ATP-binding. With cyclin, two alpha helices change position to permit ATP binding, one of them, the L12 helix that comes just before the T-loop in the primary sequence, becomes a beta strand and helps rearrange the T-loop, so it no longer blocks the active site. The other alpha helix called the PSTAIRE helix rearranges and helps change the position of the key amino acid residues in the active site, there is considerable specificity in which cyclin binds with CDK. Furthermore, cyclin binding determines the specificity of the complex for particular substrates
38.
Cyclin-dependent kinase 1
–
It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S. pombe, where it is encoded by genes cdc28 and cdc2, respectively. In humans, Cdk1 is encoded by the CDC2 gene, with its cyclin partners, Cdk1 forms complexes that phosphorylate a variety of target substrates, phosphorylation of these proteins leads to cell cycle progression. Cdk1 is a protein, and is highly conserved. The human homolog of Cdk1, CDC2, shares approximately 63% amino-acid identity with its yeast homolog, furthermore, human CDC2 is capable of rescuing fission yeast carrying a cdc2 mutation. Cdk1 is comprised mostly by the protein kinase motif, which other protein kinases share. Cdk1, like other kinases, contains a cleft in which ATP fits, substrates of Cdk1 bind near the mouth of the cleft, and Cdk1 residues catalyze the covalent bonding of the γ-phosphate to the oxygen of the hydroxyl serine/threonine of the substrate. In addition to this core, Cdk1, like other cyclin-dependent kinases, contains a T-loop. Cdk1 also contains a PSTAIRE helix, which, upon binding, moves and rearranges the active site. When bound to its partners, Cdk1 phosphorylation leads to cell cycle progression. Cdk1 activity is best understood in S. cerevisiae, so Cdk1 S. cerevisiae activity is described here, in the budding yeast, initial cell cycle entry is controlled by two regulatory complexes, SBF and MBF. These two complexes control G1/S gene transcription, however, they are normally inactive, G1/S cyclin-Cdk1 activity leads to preparation for S phase entry, and a rise in the S cyclins. Clb5, 6-Cdk1 complexes directly lead to replication origin initiation, however, they are inhibited by Sic1, cln1,2 and/or Clb5, 6-Cdk1 complex activity leads to a sudden drop in Sic1 levels, allowing for coherent S phase entry. Finally, phosphorylation by M cyclins in complex with Cdk1 leads to spindle assembly, Cdk1 phosphorylation also leads to the activation of the ubiquitin-protein ligase APCCdc20, an activation which allows for chromatid segregation and, furthermore, degradation of M-phase cyclins. This destruction of M cyclins leads to the events of mitosis. Given its essential role in cell cycle progression, Cdk1 is highly regulated, most obviously, Cdk1 is regulated by its binding with its cyclin partners. Cyclin binding alters access to the site of Cdk1, allowing for Cdk1 activity, furthermore. At least some cyclins contain a hydrophobic patch which may interact with substrates. Furthermore, cyclins can target Cdk1 to particular subcellular locations, in addition to regulation by cyclins, Cdk1 is regulated by phosphorylation
39.
Cyclin-dependent kinase 2
–
Cyclin-dependent kinase 2, also known as cell division protein kinase 2, is an enzyme that in humans is encoded by the CDK2 gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein kinases and this protein kinase is highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, also known as Cdk1 in humans. It is a subunit of the cyclin-dependent kinase complex, whose activity is restricted to the G1-S phase of the cell cycle. Its activity is regulated by phosphorylation. Two alternatively spliced variants and multiple transcription initiation sites of this gene have been reported, the role of this protein in G1-S transition has been recently questioned as cells lacking Cdk2 are reported to have no problem during this transition. Known CDK inhibitors are p21Cip1 and p27Kip1, see also the PDB gallery below showing interactions with many inhibitors In melanocytic cell types, expression of the CDK2 gene is regulated by the Microphthalmia-associated transcription factor. CDK2 human gene details in the UCSC Genome Browser
40.
Cyclin-dependent kinase 3
–
Cell division protein kinase 3 is an enzyme that in humans is encoded by the CDK3 gene. CDK3 complements cdc28 mutants of Saccharomyces cerevisiae suggesting that it may be involved in cell cycle control, CDK3 can phosphorylate histone H1 and interacts with an unknown type of cyclin. CDK3 protein, human at the US National Library of Medicine Medical Subject Headings CDK3 human gene location in the UCSC Genome Browser, CDK3 human gene details in the UCSC Genome Browser
41.
Cyclin-dependent kinase 4
–
Cyclin-dependent kinase 4 also known as cell division protein kinase 4 is an enzyme that in humans is encoded by the CDK4 gene. CDK4 is a member of the cyclin-dependent kinase family, the protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is similar to the gene products of S. cerevisiae cdc28. It is a subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase and this kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product. Ser/Thr-kinase component of cyclin D-CDK4 complexes that phosphorylate and inhibit members of the protein family including RB1. Hypophosphorylates RB1 in early G1 phase, Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity, component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex. Mutations in this gene as well as in its related proteins including D-type cyclins, p16, multiple polyadenylation sites of this gene have been reported. It is regulated by Cyclin D. Palbociclib is US FDA approved for estrogen receptor-positive advanced breast cancer, see also CDK inhibitor for inhibitors of various CDKs. CDK4 human gene details in the UCSC Genome Browser
42.
Cyclin-dependent kinase 5
–
Cell division protein kinase 5 is an enzyme that in humans is encoded by the CDK5 gene. The protein encoded by this gene is part of the cyclin-dependent kinase family, recently Cdk5 has emerged as an essential kinase in sensory pathways. Recent reports of Pareek et al. suggest its necessity in pain signaling, CDK5 is required for proper development of the brain and to be activated, CDK5 must associate with CDK5R1 or CDK5R2. Unlike other cyclin dependent kinases, CDK5 does not also require phosphorylation on the T loop so that binding with the activator is sufficient to activate the kinase, Cdk5 is involved in the processes of neuronal maturation and migration, phosphorylating the key intracellular adaptor of the reelin signaling chain. Experiments performed on mice lacking p35, an activator of cdk5 in early brain development. This disrupted lamination again implicated cdk5 in neuronal migration and plasticity, Cdk5 is also involved in the regulation of synaptic vesicle exocytosis via phosphorylation of munc-18. Blocking Cdk5 in mice helps them get over fear learned in a particular context, conversely, the learned fear persisted when the enzymes activity was increased in the hippocampus, the brains centre for storing memories. Dysregulation of this enzyme has been implicated in several diseases including Alzheimers. It is involved in invasive cancers, apparently by reducing the activity of the regulatory protein caldesmon. CDK5 was originally named NCLK due to its similar phosphorylation motif, CDK5 in combination with an activator was also referred to as Tau Protein Kinase II. Furthermore, Cdk5 has been reported to be involved in T cell activation and play an important role in development of autoimmune disorders, click on genes, proteins and metabolites below to link to respective articles. Cyclin-dependent kinase 5 has been shown to interact with LMTK2, NDEL1, CDK5R1, Nestin, cyclin-Dependent Kinase 5 at the US National Library of Medicine Medical Subject Headings CDK5 human gene location in the UCSC Genome Browser. CDK5 human gene details in the UCSC Genome Browser
43.
Cyclin-dependent kinase 6
–
Cell division protein kinase 6 is an enzyme encoded by the CDK6 gene. It is regulated by cyclins, more specifically by Cyclin D proteins, the protein encoded by this gene is a member of the cyclin-dependent kinase, family, which includes CDK4. The activity of this kinase first appears in phase, which is controlled by the regulatory subunits including D-type cyclins. This kinase, as well as CDK4, has shown to phosphorylate. The CDK6 gene is conserved in eukaryotes, including the budding yeast, the CDK6 gene is located on chromosome 7 in humans. The gene spans 231,706 base pairs and encodes a 326 amino acid protein with a kinase function, the gene is overexpressed in cancers like lymphoma, leukemia, medulloblastoma and melanoma associated with chromosomal rearrangements. The CDK6 protein contains a core composed of a serine/threonine domain. This protein also contains an ATP-binding pocket, inhibitory and activating phosphorylation sites, a PSTAIRE-like cyclin-binding domain, after binding the Cyclin in the PSTAIRE helix, the protein changes its conformational structure to expose the phosphorylation motif. The protein can be found in the cytoplasm and the nucleus, in 1994, Matthew Meyerson and Ed Harlow investigated the product of a close analogous gene of CDK4. This gene, identified as PLSTIRE was translated into a protein that interacted with the cyclins CD1, CD2 and CD3, but that was different from CDK4, the protein was then renamed CDK6 for simplicity. In mammalian cells, cell cycle is activated by CDK6 in the early G1 phase through interactions with cyclins D1, D2, there are many changes in gene expression that are regulated through this enzyme. After the complex is formed, the C-CDK6 enzymatic complex phosphorylates the protein pRb, after its phosphorylation, pRb releases its binding partner E2F, a transcriptional activator, which in turns activate DNA replication. The CDK6 complex ensures a point of switch to commit to division responding to signals, like mitogens. CDK6 is involved in a feedback loop that activates transcription factors through a reaction cascade. Importantly, these C-CDK complexes act as a kinase, phosphorylating and inactivating the protein of Rb and p-Rb related “pocket proteins” p107 and p130. While doing this, the CDK6 in conjunction with CDK4, act as a signal that first appears in G1. CDK6 is important for the control of G1 to S phase transition, in mutant Knockout mice of CDK6, the hematopoietic function is impaired, regardless of otherwise organism normal development. This might hint additional roles of CDK6 in the development of blood components, there are additional functions of CDK6 not associated with its kinase activity
44.
Cyclin-dependent kinase 7
–
Cell division protein kinase 7 is an enzyme that in humans is encoded by the CDK7 gene. The protein encoded by this gene is a member of the cyclin-dependent protein kinase family, CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression. This protein forms a complex with cyclin H and MAT1. It is a component of the transcription factor TFIIH, that is involved in transcription initiation. This protein is thought to serve as a link between the regulation of transcription and the cell cycle. CDK7 human gene details in the UCSC Genome Browser
45.
Cyclin-dependent kinase 8
–
Cell division protein kinase 8 is an enzyme that in humans is encoded by the CDK8 gene. The protein encoded by this gene is a member of the cyclin-dependent protein kinase family, CDK8 and cyclin C associate with the mediator complex and regulate transcription by several mechanisms. CDK8 binds to and/or phosphorylates several transcription factors, which can have an activating or inhibitory effect on transcription factor function, CDK8 phosphorylates the Notch intracellular domain, SREBP, and STAT1 S727. CDK8 also inhibits transcriptional activation by influencing turnover of subunits in the mediator complex tail module, in addition, CDK8 influences binding of RNA polymerase II to the mediator complex. CDK8 is a colorectal cancer oncogene, the CDK8 gene is amplified in colorectal tumors. However, CDK8 may not be oncogenic in all cell types, specifically, CDK8 promotes turnover of the notch intracellular domain, and inhibits EGFR signaling-driven cell fates in C. elegans. Thus, CDK8 may be an oncogene in cancers driven by Wnt/β-catenin signaling, the natural product cortistatin A is a potent and selective inhibitor of CDK8 and CDK19. Cyclin-dependent kinase 8 has been shown to interact with, CDK8 protein, CDK8 human gene details in the UCSC Genome Browser
46.
Cyclin-dependent kinase 9
–
Cyclin-dependent kinase 9 or CDK9 is a cyclin-dependent kinase associated with P-TEFb. The protein encoded by this gene is a member of the cyclin-dependent kinase family, CDK family members are highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, and known as important cell cycle regulators. CDK9 is also known to associate with proteins such as TRAF2. CDK9 human gene details in the UCSC Genome Browser
. PMID 16488869. doi:10.1016/j.cub.2005.12.043.
Media related to Anaphase at Wikimedia Commons
