The immune system is a host defense system comprising many biological structures and processes within an organism that protects against disease. To function properly, an immune system must detect a wide variety of agents, known as pathogens, from viruses to parasitic worms, distinguish them from the organism's own healthy tissue. In many species, the immune system can be classified into subsystems, such as the innate immune system versus the adaptive immune system, or humoral immunity versus cell-mediated immunity. In humans, the blood–brain barrier, blood–cerebrospinal fluid barrier, similar fluid–brain barriers separate the peripheral immune system from the neuroimmune system, which protects the brain. Pathogens can evolve and adapt, thereby avoid detection and neutralization by the immune system. Simple unicellular organisms such as bacteria possess a rudimentary immune system in the form of enzymes that protect against bacteriophage infections. Other basic immune mechanisms evolved in ancient eukaryotes and remain in their modern descendants, such as plants and invertebrates.
These mechanisms include phagocytosis, antimicrobial peptides called defensins, the complement system. Jawed vertebrates, including humans, have more sophisticated defense mechanisms, including the ability to adapt over time to recognize specific pathogens more efficiently. Adaptive immunity creates immunological memory after an initial response to a specific pathogen, leading to an enhanced response to subsequent encounters with that same pathogen; this process of acquired immunity is the basis of vaccination. Disorders of the immune system can result in inflammatory diseases and cancer. Immunodeficiency occurs when the immune system is less active than normal, resulting in recurring and life-threatening infections. In humans, immunodeficiency can either be the result of a genetic disease such as severe combined immunodeficiency, acquired conditions such as HIV/AIDS, or the use of immunosuppressive medication. In contrast, autoimmunity results from a hyperactive immune system attacking normal tissues as if they were foreign organisms.
Common autoimmune diseases include Hashimoto's thyroiditis, rheumatoid arthritis, diabetes mellitus type 1, systemic lupus erythematosus. Immunology covers the study of all aspects of the immune system; the immune system protects organisms from infection with layered defenses of increasing specificity. In simple terms, physical barriers prevent pathogens such as bacteria and viruses from entering the organism. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all animals. If pathogens evade the innate response, vertebrates possess a second layer of protection, the adaptive immune system, activated by the innate response. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen; this improved response is retained after the pathogen has been eliminated, in the form of an immunological memory, allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered.
Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-self molecules. In immunology, self molecules are those components of an organism's body that can be distinguished from foreign substances by the immune system. Conversely, non-self molecules are those recognized as foreign molecules. One class of non-self molecules are called antigens and are defined as substances that bind to specific immune receptors and elicit an immune response. Newborn infants have no prior exposure to microbes and are vulnerable to infection. Several layers of passive protection are provided by the mother. During pregnancy, a particular type of antibody, called IgG, is transported from mother to baby directly through the placenta, so human babies have high levels of antibodies at birth, with the same range of antigen specificities as their mother. Breast milk or colostrum contains antibodies that are transferred to the gut of the infant and protect against bacterial infections until the newborn can synthesize its own antibodies.
This is passive immunity because the fetus does not make any memory cells or antibodies—it only borrows them. This passive immunity is short-term, lasting from a few days up to several months. In medicine, protective passive immunity can be transferred artificially from one individual to another via antibody-rich serum. Microorganisms or toxins that enter an organism encounter the cells and mechanisms of the innate immune system; the innate response is triggered when microbes are identified by pattern recognition receptors, which recognize components that are conserved among broad groups of microorganisms, or when damaged, injured or stressed cells send out alarm signals, many of which are recognized by the same receptors as those that recognize pathogens. Innate immune defenses are non-specific, meaning these systems respond to pathogens in a generic way; this system does not confer long-lasting immunity against a pathogen. The innate immune system is the dominant system of host defense in most organisms.
Cells in innate immune system recognizes use pattern recognition receptors to recognize molecular structures that are produced by microbial pathogens. PRRs are germline-encoded host sensors, they are proteins expressed by cells of the innate immune system, such as dendritic cells, macrophages, m
Secretion is the movement of material from one point to another, e.g. secreted chemical substance from a cell or gland. In contrast, excretion, is the removal of certain substances or waste products from a cell or organism; the classical mechanism of cell secretion is via secretory portals at the cell plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structure at the cell plasma membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell. Secretion in bacterial species means the transport or translocation of effector molecules for example: proteins, enzymes or toxins from across the interior of a bacterial cell to its exterior. Secretion is a important mechanism in bacterial functioning and operation in their natural surrounding environment for adaptation and survival. Eukaryotic cells, including human cells, have a evolved process of secretion. Proteins targeted for the outside are synthesized by ribosomes docked to the rough endoplasmic reticulum.
As they are synthesized, these proteins translocate into the ER lumen, where they are glycosylated and where molecular chaperones aid protein folding. Misfolded proteins are identified here and retrotranslocated by ER-associated degradation to the cytosol, where they are degraded by a proteasome; the vesicles containing the properly folded proteins enter the Golgi apparatus. In the Golgi apparatus, the glycosylation of the proteins is modified and further posttranslational modifications, including cleavage and functionalization, may occur; the proteins are moved into secretory vesicles which travel along the cytoskeleton to the edge of the cell. More modification can occur in the secretory vesicles. There is vesicle fusion with the cell membrane at a structure called the porosome, in a process called exocytosis, dumping its contents out of the cell's environment. Strict biochemical control is maintained over this sequence by usage of a pH gradient: the pH of the cytosol is 7.4, the ER's pH is 7.0, the cis-golgi has a pH of 6.5.
Secretory vesicles have pHs ranging between 5.0 and 6.0. There are many proteins like FGF2, interleukin-1 etc. which do not have a signal sequence. They do not use the classical ER-golgi pathway; these are secreted through various nonclassical pathways. At least four nonclassical protein secretion pathways have been described, they include 1) direct translocation of proteins across the plasma membrane through membrane transporters, 2) blebbing, 3) lysosomal secretion, 4) release via exosomes derived from multivesicular bodies. In addition, proteins can be released from cells by mechanical or physiological wounding and through nonlethal, transient oncotic pores in the plasma membrane induced by washing cells with serum-free media or buffers. Many human cell types have the ability to be secretory cells, they have a well-developed endoplasmic reticulum and Golgi apparatus to fulfill their function. Tissues in humans that produce secretions include the gastrointestinal tract which secretes digestive enzymes and gastric acid, the lung which secretes surfactants, sebaceous glands which secrete sebum to lubricate the skin and hair.
Meibomian glands in the eyelid secrete sebum to protect the eye. Secretion is not unique to eukaryotes alone - it is present in bacteria and archaea as well. ATP binding cassette type transporters are common to all the three domains of life; the Sec system constituting the Sec Y-E-G complex is another conserved secretion system, homologous to the translocon in the eukaryotic endoplasmic reticulum and the Sec 61 translocon complex of yeast. Some secreted proteins are translocated across the cytoplasmic membrane by the Sec translocon, which requires the presence of an N-terminal signal peptide on the secreted protein. Others are translocated across the cytoplasmic membrane by the twin-arginine translocation pathway. Gram-negative bacteria have two membranes. There are at least six specialized secretion systems in gram-negative bacteria. Many secreted proteins are important in bacterial pathogenesis. Type I secretion is a chaperone dependent secretion system employing the Tol gene clusters; the process begins as a leader sequence HlyA binds HlyB on the membrane.
This signal sequence is specific for the ABC transporter. The HlyAB complex stimulates HlyD which begins to uncoil and reaches the outer membrane where TolC recognizes a terminal molecule or signal on HlyD. HlyD recruits TolC to the inner membrane and HlyA is excreted outside of the outer membrane via a long-tunnel protein channel. Type I secretion system transports various molecules, from ions, drugs, to proteins of various sizes; the molecules secreted vary in size from the small Escherichia coli peptide colicin V, to the Pseudomonas fluorescens cell adhesion protein LapA of 520 kDa. The best characterized are the lipases. Type I secretion is involved in export of non-proteinaceous substrates like cyclic β-glucans and polysaccharides. Proteins secreted through the type II system, or main terminal branch of the general secretory pathway, depend on the Sec or Tat system for initial transport into the periplasm. Once there, they pass through the outer membrane via a multimeric complex of pore forming secretin proteins.
In addition to the secretin protein, 10–15 other inner and outer memb
Deoxyribonucleic acid is a molecule composed of two chains that coil around each other to form a double helix carrying the genetic instructions used in the growth, development and reproduction of all known organisms and many viruses. DNA and ribonucleic acid are nucleic acids; the two DNA strands are known as polynucleotides as they are composed of simpler monomeric units called nucleotides. Each nucleotide is composed of one of four nitrogen-containing nucleobases, a sugar called deoxyribose, a phosphate group; the nucleotides are joined to one another in a chain by covalent bonds between the sugar of one nucleotide and the phosphate of the next, resulting in an alternating sugar-phosphate backbone. The nitrogenous bases of the two separate polynucleotide strands are bound together, according to base pairing rules, with hydrogen bonds to make double-stranded DNA; the complementary nitrogenous bases are divided into two groups and purines. In DNA, the pyrimidines are cytosine. Both strands of double-stranded DNA store the same biological information.
This information is replicated as and when the two strands separate. A large part of DNA is non-coding, meaning that these sections do not serve as patterns for protein sequences; the two strands of DNA are thus antiparallel. Attached to each sugar is one of four types of nucleobases, it is the sequence of these four nucleobases along the backbone. RNA strands are created using DNA strands as a template in a process called transcription. Under the genetic code, these RNA strands specify the sequence of amino acids within proteins in a process called translation. Within eukaryotic cells, DNA is organized into long structures called chromosomes. Before typical cell division, these chromosomes are duplicated in the process of DNA replication, providing a complete set of chromosomes for each daughter cell. Eukaryotic organisms store most of their DNA inside the cell nucleus as nuclear DNA, some in the mitochondria as mitochondrial DNA, or in chloroplasts as chloroplast DNA. In contrast, prokaryotes store their DNA only in circular chromosomes.
Within eukaryotic chromosomes, chromatin proteins, such as histones and organize DNA. These compacting structures guide the interactions between DNA and other proteins, helping control which parts of the DNA are transcribed. DNA was first isolated by Friedrich Miescher in 1869, its molecular structure was first identified by Francis Crick and James Watson at the Cavendish Laboratory within the University of Cambridge in 1953, whose model-building efforts were guided by X-ray diffraction data acquired by Raymond Gosling, a post-graduate student of Rosalind Franklin. DNA is used by researchers as a molecular tool to explore physical laws and theories, such as the ergodic theorem and the theory of elasticity; the unique material properties of DNA have made it an attractive molecule for material scientists and engineers interested in micro- and nano-fabrication. Among notable advances in this field are DNA origami and DNA-based hybrid materials. DNA is a long polymer made from repeating units called nucleotides.
The structure of DNA is dynamic along its length, being capable of coiling into tight loops and other shapes. In all species it is composed of two helical chains, bound to each other by hydrogen bonds. Both chains are coiled around the same axis, have the same pitch of 34 angstroms; the pair of chains has a radius of 10 angstroms. According to another study, when measured in a different solution, the DNA chain measured 22 to 26 angstroms wide, one nucleotide unit measured 3.3 Å long. Although each individual nucleotide is small, a DNA polymer can be large and contain hundreds of millions, such as in chromosome 1. Chromosome 1 is the largest human chromosome with 220 million base pairs, would be 85 mm long if straightened. DNA does not exist as a single strand, but instead as a pair of strands that are held together; these two long strands coil in the shape of a double helix. The nucleotide contains both a segment of the backbone of a nucleobase. A nucleobase linked to a sugar is called a nucleoside, a base linked to a sugar and to one or more phosphate groups is called a nucleotide.
A biopolymer comprising multiple linked nucleotides is called a polynucleotide. The backbone of the DNA strand is made from alternating sugar residues; the sugar in DNA is 2-deoxyribose, a pentose sugar. The sugars are joined together by phosphate groups that form phosphodiester bonds between the third and fifth carbon atoms of adjacent sugar rings; these are known as the 3′-end, 5′-end carbons, the prime symbol being used to distinguish these carbon atoms from those of the base to which the deoxyribose forms a glycosidic bond. When imagining DNA, each phosphoryl is considered to "belong" to the nucleotide whose 5′ carbon forms a bond therewith. Any DNA strand therefore has one end at which there is a phosphoryl attached to the 5′ carbon of a ribose and another end a
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, providing structure to cells and organisms, transporting molecules from one location to another. Proteins differ from one another in their sequence of amino acids, dictated by the nucleotide sequence of their genes, which results in protein folding into a specific three-dimensional structure that determines its activity. 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 considered to be proteins and are called peptides, or sometimes oligopeptides; the individual amino acid residues are bonded together by peptide bonds and adjacent amino acid residues. The sequence of amino acid residues in a protein is defined by the sequence of a gene, encoded in the genetic code.
In general, the genetic code specifies 20 standard amino acids. Shortly after or during synthesis, the residues in a protein are chemically modified by post-translational modification, which alters the physical and chemical properties, stability and the function of the proteins. Sometimes proteins have non-peptide groups attached, which can be called prosthetic groups or cofactors. Proteins can work together to achieve a particular function, they associate to form stable protein complexes. Once formed, proteins only exist for a certain period and are degraded and recycled by the cell's machinery through the process of protein turnover. A protein's lifespan covers a wide range, they can exist for years with an average lifespan of 1 -- 2 days in mammalian cells. Abnormal or misfolded proteins are degraded more either 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 and participate in every process within cells.
Many proteins are enzymes that are vital to metabolism. Proteins have structural or mechanical functions, such as actin and myosin in muscle and the proteins in the cytoskeleton, which form a system of scaffolding that maintains cell shape. Other proteins are important in cell signaling, immune responses, cell adhesion, 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. Proteins may be purified from other cellular components using a variety of techniques such as ultracentrifugation, precipitation and chromatography. Methods used to study protein structure and function include immunohistochemistry, site-directed mutagenesis, X-ray crystallography, nuclear magnetic resonance and mass spectrometry. 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, a variable side chain are bonded.
Only proline differs from this basic structure as it contains an unusual ring to the N-end amine group, which forces the CO–NH amide moiety into a fixed conformation. The side chains of the standard amino acids, detailed in the list of standard amino acids, have a great variety of chemical structures and properties; the amino acids in a polypeptide chain are linked by peptide bonds. Once linked in the protein chain, an individual amino acid is called a residue, the linked series of carbon and oxygen atoms are known as the main chain or protein backbone; the peptide bond has two resonance forms that contribute some double-bond character and inhibit rotation around its axis, so that the alpha carbons are coplanar. The other two dihedral angles in the peptide bond determine the local shape assumed by the protein backbone; the end with a free amino group is known as the N-terminus or amino terminus, whereas the end of the protein with a free carboxyl group is known as the C-terminus or carboxy terminus.
The words protein and peptide are a little ambiguous and can overlap in meaning. Protein is used to refer to the complete biological molecule in a stable conformation, whereas peptide is reserved for a short amino acid oligomers lacking a stable three-dimensional structure. However, the boundary between the two is not well defined and lies near 20–30 residues. Polypeptide can refer to any single linear chain of amino acids regardless of length, but implies an absence of a defined conformation. Proteins can interact with many types of molecules, including with other proteins, with lipids, with carboyhydrates, with DNA, it has been estimated. Smaller bacteria, such as Mycoplasma or spirochetes contain fewer molecules, on the order of 50,000 to 1 million. By contrast, eukaryotic cells are larger and thus contain much more pro
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells. ILs can be divided into four major groups based on distinguishing structural features. However, their amino acid sequence similarity is rather weak; the human genome encodes related proteins. The function of the immune system depends in a large part on interleukins, rare deficiencies of a number of them have been described, all featuring autoimmune diseases or immune deficiency; the majority of interleukins are synthesized by helper CD4 T lymphocytes, as well as through monocytes and endothelial cells. They promote the development and differentiation of T and B lymphocytes, hematopoietic cells. Interleukin receptors on astrocytes in the hippocampus are known to be involved in the development of spatial memories in mice; the name "interleukin" was chosen in 1979, to replace the various different names used by different research groups to designate interleukin 1 and interleukin 2. This decision was taken during the Second International Lymphokine Workshop in Switzerland.
The term interleukin derives from "as a means of communication", "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes". The name is something of a relic; the term was coined by University of Victoria. Some interleukins are classified as lymphokines, lymphocyte-produced cytokines that mediate immune responses. Interleukin 1 alpha and interleukin 1 beta are cytokines that participate in the regulation of immune responses, inflammatory reactions, hematopoiesis. Two types of IL-1 receptor, each with three extracellular immunoglobulin -like domains, limited sequence similarity and different pharmacological characteristics have been cloned from mouse and human cell lines: these have been termed type I and type II receptors; the receptors both exist in transmembrane and soluble forms: the soluble IL-1 receptor is thought to be post-translationally derived from cleavage of the extracellular portion of the membrane receptors. Both IL-1 receptors appear to be well conserved in evolution, map to the same chromosomal location.
The receptors can both bind all three forms of IL-1. The crystal structures of IL1A and IL1B have been solved, showing them to share the same 12-stranded beta-sheet structure as both the heparin binding growth factors and the Kunitz-type soybean trypsin inhibitors; the beta-sheets are arranged in 4 similar lobes around a central axis, 8 strands forming an anti-parallel beta-barrel. Several regions the loop between strands 4 and 5, have been implicated in receptor binding. Molecular cloning of the Interleukin 1 Beta converting enzyme is generated by the proteolytic cleavage of an inactive precursor molecule. A complementary DNA encoding protease that carries out this cleavage has been cloned. Recombinant expression enables cells to process precursor Interleukin 1 Beta to the mature form of the enzyme. Interleukin 1 plays a role in the Central Nervous System. Research indicates that mice with a genetic deletion of the type I IL-1 receptor display markedly impaired hippocampal-dependent memory functioning and Long-term potentiation, although memories that do not depend on the integrity of the hippocampus seem to be spared.
However, when mice with this genetic deletion have wild-type neural precursor cells injected into their hippocampus and these cells are allowed to mature into astrocytes containing the interleukin-1 receptors, the mice exhibit normal hippocampal-dependent memory function, partial restoration of long-term potentiation. T lymphocytes regulate the growth and differentiation of T cells and certain B cells through the release of secreted protein factors; these factors, which include interleukin 2, are secreted by lectin- or antigen-stimulated T cells, have various physiological effects. IL2 is a lymphokine. In addition, it acts on some B cells, via receptor-specific binding, as a growth factor and antibody production stimulant; the protein is secreted as a single glycosylated polypeptide, cleavage of a signal sequence is required for its activity. Solution NMR suggests that the structure of IL2 comprises a bundle of 4 helices, flanked by 2 shorter helices and several poorly defined loops. Residues in helix A, in the loop region between helices A and B, are important for receptor binding.
Secondary structure analysis has suggested similarity to IL4 and granulocyte-macrophage colony stimulating factor. Interleukin 3 is a cytokine that regulates hematopoiesis by controlling the production and function of granulocytes and macrophages; the protein, which exists in vivo as a monomer, is produced in activated T cells and mast cells, is activated by the cleavage of an N-terminal signal sequence. IL3 is produced by T lymphocytes and T-cell lymphomas only after stimulation with antigens, mitogens, or chemical activators such as phorbol esters. However, IL3 is constitutively expressed in the myelomonocytic leukaemia cell line WEHI-3B, it is thought that the genetic change of the cell line to constitutive production of IL3 is the key event in development of this leukaemia. Interleukin 4 is produced by CD4+ T cells specialized in providing he
Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, is a protective response involving immune cells, blood vessels, molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, initiate tissue repair; the five classical signs of inflammation are heat, redness and loss of function. Inflammation is a generic response, therefore it is considered as a mechanism of innate immunity, as compared to adaptive immunity, specific for each pathogen. Too little inflammation could lead to progressive tissue destruction by the harmful stimulus and compromise the survival of the organism. In contrast, chronic inflammation may lead to a host of diseases, such as hay fever, atherosclerosis, rheumatoid arthritis, cancer. Inflammation is therefore closely regulated by the body. Inflammation can be classified as either chronic.
Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A series of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation, such as mononuclear cells, is characterized by simultaneous destruction and healing of the tissue from the inflammatory process. Inflammation is not a synonym for infection. Infection describes the interaction between the action of microbial invasion and the reaction of the body's inflammatory response—the two components are considered together when discussing an infection, the word is used to imply a microbial invasive cause for the observed inflammatory reaction. Inflammation on the other hand describes purely the body's immunovascular response, whatever the cause may be.
But because of how the two are correlated, words ending in the suffix -itis are sometimes informally described as referring to infection. For example, the word urethritis means only "urethral inflammation", but clinical health care providers discuss urethritis as a urethral infection because urethral microbial invasion is the most common cause of urethritis, it is useful to differentiate inflammation and infection because there are typical situations in pathology and medical diagnosis where inflammation is not driven by microbial invasion – for example, trauma and autoimmune diseases including type III hypersensitivity. Conversely, there is pathology where microbial invasion does not cause the classic inflammatory response – for example, parasitosis or eosinophilia. Acute inflammation is a short-term process appearing within a few minutes or hours and begins to cease upon the removal of the injurious stimulus, it involves a coordinated and systemic mobilization response locally of various immune and neurological mediators of acute inflammation.
In a normal healthy response, it becomes activated, clears the pathogen and begins a repair process and ceases. It is characterized by five cardinal signs:An acronym that may be used to remember the key symptoms is "PRISH", for pain, immobility and heat; the traditional names for signs of inflammation come from Latin: Dolor Calor Rubor Tumor Functio laesa The first four were described by Celsus, while loss of function was added by Galen. However, the addition of this fifth sign has been ascribed to Thomas Sydenham and Virchow. Redness and heat are due to increased blood flow at body core temperature to the inflamed site. Loss of function has multiple causes. Acute inflammation of the lung does not cause pain unless the inflammation involves the parietal pleura, which does have pain-sensitive nerve endings; the process of acute inflammation is initiated by resident immune cells present in the involved tissue resident macrophages, dendritic cells, Kupffer cells and mast cells. These cells possess surface receptors known as pattern recognition receptors, which recognize two subclasses of molecules: pathogen-associated molecular patterns and damage-associated molecular patterns.
PAMPs are compounds that are associated with various pathogens, but which are distinguishable from host molecules. DAMPs are compounds that are associated with host-related cell damage. At the onset of an infection, burn, or other injuries, these cells undergo activation and release inflammatory mediators responsible for the clinical signs of inflammation. Vasodilation and its resulting increased blood flow causes increased heat. Increased permeability of the blood vessels results in an exudation of plasma proteins and fluid into the tissue, which manifests itself as swelling; some of the released mediators such as bradykinin increase the sensitivity to pain. The mediator molecules alter the blood vessels to
The term cell growth is used in the contexts of biological cell development and cell division. When used in the context of cell development, the term refers to increase in cytoplasmic and organelle volume, as well as increase in genetic material following the replication during S phase; this is not to be confused with growth in the context of cell division, referred to as proliferation, where a cell, known as the "mother cell", grows and divides to produce two "daughter cells". Cell populations go through a particular type of exponential growth called doubling. Thus, each generation of cells should be twice as numerous as the previous generation. However, the number of generations only gives a maximum figure as not all cells survive in each generation. Cell size is variable among organisms, with some algae such as Caulerpa taxifolia being a single cell several meters in length. Plant cells are much larger than animal cells, protists such as Paramecium can be 330 μm long, while a typical human cell might be 10 μm.
How these cells "decide" how big they should be before dividing is an open question. Chemical gradients are known to be responsible, it is hypothesized that mechanical stress detection by cytoskeletal structures is involved. Work on the topic requires an organism whose cell cycle is well-characterized; the relationship between cell size and cell division has been extensively studied in yeast. For some cells, there is a mechanism by which cell division is not initiated until a cell has reached a certain size. If the nutrient supply is restricted, the rate of increase in cell size is slowed, the time period between cell divisions is increased. Yeast cell-size mutants were isolated that begin cell division before reaching a normal/regular size. Wee1 protein is a tyrosine kinase that phosphorylates the Cdc2 cell cycle regulatory protein, a cyclin-dependent kinase, on a tyrosine residue. Cdc2 drives entry into mitosis by phosphorylating a wide range of targets; this covalent modification of the molecular structure of Cdc2 inhibits the enzymatic activity of Cdc2 and prevents cell division.
Wee1 acts to keep Cdc2 inactive during early G2. When cells have reached sufficient size during G2, the phosphatase Cdc25 removes the inhibitory phosphorylation, thus activates Cdc2 to allow mitotic entry. A balance of Wee1 and Cdc25 activity with changes in cell size is coordinated by the mitotic entry control system, it has been shown in Wee1 mutants, cells with weakened Wee1 activity, that Cdc2 becomes active when the cell is smaller. Thus, mitosis occurs; this suggests that cell division may be regulated in part by dilution of Wee1 protein in cells as they grow larger. The protein kinase Cdr2 and the Cdr2-related kinase Cdr1 are localized to a band of cortical nodes in the middle of interphase cells. After entry into mitosis, cytokinesis factors such as myosin II are recruited to similar nodes. A uncharacterized protein, Blt1, was found to colocalize with Cdr2 in the medial interphase nodes. Blt1 knockout cells had increased length at division, consistent with a delay in mitotic entry; this finding connects a physical location, a band of cortical nodes, with factors that have been shown to directly regulate mitotic entry, namely Cdr1, Cdr2, Blt1.
Further experimentation with GFP-tagged proteins and mutant proteins indicates that the medial cortical nodes are formed by the ordered, Cdr2-dependent assembly of multiple interacting proteins during interphase. Cdr2 is at the top of this hierarchy and works upstream of Cdr1 and Blt1. Mitosis is promoted by the negative regulation of Wee1 by Cdr2, it has been shown that Cdr2 recruits Wee1 to the medial cortical node. The mechanism of this recruitment has yet to be discovered. A Cdr2 kinase mutant, able to localize properly despite a loss of function in phosphorylation, disrupts the recruitment of Wee1 to the medial cortex and delays entry into mitosis. Thus, Wee1 localizes with its inhibitory network, which demonstrates that mitosis is controlled through Cdr2-dependent negative regulation of Wee1 at the medial cortical nodes. Cell polarity factors positioned at the cell tips provide spatial cues to limit Cdr2 distribution to the cell middle. In fission yeast Schizosaccharomyces pombe, cells divide at a defined, reproducible size during mitosis because of the regulated activity of Cdk1.
The cell polarity protein kinase Pom1, a member of the dual-specificity tyrosine-phosphorylation regulated kinase family of kinases, localizes to cell ends. In Pom1 knockout cells, Cdr2 was no longer restricted to the cell middle, but was seen diffusely through half of the cell. From this data it becomes apparent that Pom1 provides inhibitory signals that confine Cdr2 to the middle of the cell, it has been further shown that Pom1-dependent signals lead to the phosphorylation of Cdr2. Pom1 knockout cells were shown to divide at a smaller size than wild-type, which indicates a premature entry into mitosis. Pom1 forms polar gradients that peak at cell ends, which shows a direct link between size control factors and a specific physical location in the cell; as a cell grows in size, a gradient in Pom1 grows. When cells are small, Pom1 is spread diffusely throughout the cell body; as the cell increases in size, Pom1 concentration decreases in the middle and becomes concentrated at cell ends. Small cells in early G2 which contain sufficient levels of Pom1 in the entirety of the cell have inac