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UNC-Chapel Hill ENVR 442 - Mechanisms of Cell Proliferation

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1Mechanisms ofMechanisms ofCell ProliferationCell Proliferation2Cell CycleCell CycleG1G2S3• Multi-cellular organisms depend on cell division/proliferation;• Each organism has a developmental plan that determines its behavior and properties;determines its behavior and properties;• Differentiation gives rise to populations of cells which specialize in specific functions;• Almost every cell population in the adult multi-cellular organism is specified by its lineage and environment;• Within the mature organism, cells refrain from exerting their intrinsic potential to grow and divide beyond territories and patterns laid down in the overall developmental plan.• Growth factor dependence: proliferation depends on availability of tissue-type specific growth factors, which are signals, not nutrients. In many cases, factor withdrawal leads to apoptosis. •Anchorage dependence:proliferation requires interaction ofNormal:Anchorage dependence:proliferation requires interaction of transmembrane proteins called integrins with components of the extracellular matrix (ECM) components. Specific integrins recognize specific ECM molecules. • Contact inhibition: contact with like cell types inhibits cell movement and proliferation. Contact inhibition of growth limits division in culture when cells form a contiguous monolayer. Contact inhibition of movement affects the cytoskeletal organization and ygmotility of cells in a monolayer. Contact with unlike cells allows motility and hence spontaneous cell sorting. • Limited proliferation capacity: vertebrate somatic cells divide a limited number of times (ca. 50-70 divisions for human cells) before the cells enter a senescent state that maintains metabolic activity but stops all further division.4Disruption of normal cell proliferation:due to -- mutant alleles inherited from parents,-- somatic mutations arising in the organism,-- epigenetic changes which alter expression levels of key genes• Immortalization and aneuploidy: diploid cells grown to the point of senescence sometimes give rise to clonal lines that survive and grow continuously beyond normal limits;• Partial or complete loss of growth factor dependence: transformed cells may gain the ability to grow on less rich serum, or at lower initial cell density;• Loss of contact inhibition of growth: Transformed cells may overgrow monolayers and pile up onto each other (foci);overgrow monolayers and pile up onto each other (foci);• Loss of anchorage dependence: Cells may grow on soft agar or in suspension rather attached to a substrate;• Loss of contact inhibition of movement: Transformed cells maintain a motile phenotype, which may be a consequence of failure to respond properly to cell-cell adhesion signals.For human fibroblasts, after 50-70 divisions, cells enter a state of replicative senescence in which cells are metabolically active but cease to proliferate The immediate cause is a strong block to cell cycleare metabolically active, but cease to proliferate. The immediate cause is a strong block to cell cycle progression and entry to S phase, mediated by cyclin kinase inhibitors (CKI) such as p16INK4Aand p21CIP1. Cells can be forced to bypass senescence by suppression of the pRB and p53 replication regulators, e.g. by the action of viral oncogenes such as SV40 large T or adenovirus E1A. Cells thus forced to continue to divide reach a second proliferative block known as replicative crisis, characterized by drastic chromosomal instability, leading almost invariably to cell death.The limit of some 50-70 division cycles for human diploid fibroblasts is mediated by telomere length. The telomere is an extension of DNA at chromosome ends, generated by the telomerase reverse transcriptase, (TERT), which uses an internally bound RNA loop as a template. The replication process terminates before the end of the lagging strand, and telomeres thus shorten with each division unless maintained by telomerase. Telomerase is active in germline cells, but inactive in somatic cells. Telomere length correlates with age of cells in culture, and with age in the organism.Cells reach senescence when the short telomeres trigger the protective mechanisms of p53, which stimulates the CKIs to halt further cell cycle progress. Cells reach crisis when telomeres are lost, exposing chromosome ends, and provoking the double strand repair mechanism to make inappropriate attempts at recombination and ligation In some cases, immortalized cells maintain telomeres by reactivating telomerase, and maintain relatively stable chromosomes. However, a significant proportion of immortalized cells are viable in the absence of telomerase, and use a less well characterized process alternative maintenance of telomeres (ALT). www.chembio.uoguelph.ca5Free Radic Biol Med. 2008 44(3):235-46 CDKs and their role in cell-cycle:During G1, the levels of G1cyclins rise, and theseliitithliddtkicyclins associatewithcyclin-dependentkinases(CDKs). Activity of G1CDKspromotesthepassage of cells through START (budding yeast),also known as the restriction point (R) in fissionyeast and higher eukaryotes. After passingthrough this point, a cell is committed to continuethrough the cell cycle.Nature Reviews Molecular Cell Biology 2; 815-826 (2001)6Three-layer regulation of the cell cycle.Cell-cycle control can be described as a 3-layer process. The immediate phenomena of the cell cycle, including DNA synthesis and chromosome separation (layer a), are qualitatively controlled by phosphorylation. Movement through the cycle (layer b) depends on the activity of cyclin-dependent kinases (CDKs), which are promoted by accelerators — cyclins — and antagonized by brakes — CDK inhibitors (CKIs). The protein levels of cyclins, CKIs and many other cell-cycle-related regulators are quantitatively controlled by ubiquitylating enzymes (layer c).Nakayama & Nakayama, Nat Rev Cancer 2006Major Cell Cycle Regulatory ProteinsMajor Cell Cycle Regulatory Proteins7Evolution of DNA damage during the cell cycle8Cell Cycle CheckpointsCell Cycle CheckpointsMMSSGG11GG22MMG1Delay G2DelayIRDNA DamageATM/ATRUV IR DNA DamageATR ATM p53 CHK1 p21/14-3-3 CDC25C Cyclin B1 / CDC2p53 CHK2 p21Cyclin / CDK’sPlk-1Crm19Function of p53 in response to DNA DamageFunction of p53 in response to DNA DamageATR is an essential checkpoint kinaseAtaxia telangiectasia- and rad3-relatedATR-null embryos die at day 3 with severe chromosomal damageExpression of kinase-inactive


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