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Cell cycle
From Wikipedia, the free encyclopedia For the separation of chromosomes that occurs as part of the cell cycle, see mitosis. For the Academic journal, see Cell Cycle.
Each turn of the cell cycle divides the chromosomes in a cell nucleus. The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication (replication). In cells without a nucleus (prokaryotic), the cell cycle occurs via a process termed binary fission. In cells with a nucleus (eukaryotes), the cell cycle can be divided in two brief periods: interphaseduring which the cell grows, accumulating nutrients needed for mitosis and duplicating its DNAand the mitosis (M) phase, during which the cell splits itself into two distinct cells, often called "daughter cells". The cell-division cycle is a vital process by which a single-celled fertilized egg develops into a mature organism, as well as the process by which hair, skin, blood cells, and some internal organs are renewed.
Contents
[hide]
1 Phases
3 Checkpoints 4 Role in tumor formation 5 Synchronization of cell cultures 6 See also 7 References 8 Further reading 9 External links
[edit] Phases
The cell cycle consists of four distinct phases: G1 phase, S phase (synthesis), G2 phase (collectively known as interphase) and M phase (mitosis). M phase is itself composed of two tightly coupled processes: mitosis, in which the cell's chromosomes are divided between the two daughter cells, and cytokinesis, in which the cell's cytoplasm divides in half forming distinct cells. Activation of each phase is dependent on the proper 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.
Schematic of the cell cycle. outer ring: I = Interphase, M = Mitosis; inner ring: M = Mitosis, G1 = Gap 1, G2 = Gap 2, S = Synthesis; not in ring: G0 = Gap 0/Resting.[1] State Phase Abbreviation Description quiescent/ senescent Interphase Gap 0 Gap 1 G0 G1 A resting phase where the cell has left the cycle and has stopped dividing. Cells increase in size in Gap 1. The G1 checkpoint control mechanism ensures that everything is ready for DNA synthesis.
Synthesis
DNA replication occurs during this phase. During the gap between DNA synthesis and mitosis, the cell will continue to grow. The G2 checkpoint control mechanism ensures that everything is ready to enter the M (mitosis) phase and divide. Cell growth stops at this stage and cellular energy is focused on the orderly division into two daughter cells. A checkpoint in the middle of mitosis (Metaphase Checkpoint) ensures that the cell is ready to complete cell division.
Gap 2
G2
Cell division
Mitosis
After cell division, each of the daughter cells begin the interphase of a new cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of cell division.
[edit] Interphase
Before a cell can enter cell division, it needs to take in nutrients. All of the preparations are done during the interphase. Interphase proceeds in three stages, G1, S, and G2. Cell division operates in a cycle. Therefore, interphase is preceded by the previous cycle of mitosis and cytokinesis. Interphase is also known as preparatory phase, in this stage nucleus and cytochrome division does not occur. [edit] G1 phase The first phase within interphase, from the end of the previous M phase until the beginning of DNA synthesis is called G1 (G indicating gap). It is also called the growth phase. During this phase the biosynthetic activities of the cell, which had been considerably slowed down during M phase, resume at a high rate. This phase is marked by synthesis of various enzymes that are required in S phase, mainly those needed for DNA replication. Duration of G1 is highly variable, even among different cells of the same species.[2] [edit] S phase The ensuing S phase starts when DNA synthesis commences; when it is complete, all of the chromosomes have been replicated, i.e., each chromosome has two (sister) chromatids. Thus, during this phase, the amount of DNA in the cell has effectively doubled, though the ploidy of the cell remains the same. Rates of RNA transcription and protein synthesis are very low during this phase[citation needed]. An exception to this is histone production, most of which appears during the S phase.[3][4][5] [edit] G2 phase The cell then enters the G2 phase, which lasts until the cell enters mitosis. Again, significant biosynthesis occurs during this phase, mainly involving the production of microtubules,
which are required during the process of mitosis. Inhibition of protein synthesis during G2 phase prevents the cell from undergoing mitosis.
prophase, metaphase, anaphase, telophase cytokinesis (strictly speaking, cytokinesis is not part of mitosis but is an event that directly follows mitosis in which cytoplasm is divided into two daughter cells)
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets in two nuclei.[6] It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly equal shares of these cellular components. Mitosis and cytokinesis together define the mitotic (M) phase of the cell cycle - the division of the mother cell into two daughter cells, genetically identical to each other and to their parent cell. This accounts for approximately 10% of the cell cycle. Mitosis occurs exclusively in eukaryotic cells, but occurs in different ways in different species. For example, animals undergo an "open" mitosis, where the nuclear envelope breaks down before the chromosomes separate, while fungi such as Aspergillus nidulans and Saccharomyces cerevisiae (yeast) undergo a "closed" mitosis, where chromosomes divide within an intact cell nucleus.[7] Prokaryotic cells, which lack a nucleus, divide by a process called binary fission. The process of mitosis is complex and highly regulated. The sequence of events is divided into phases, corresponding to the completion of one set of activities and the start of the next. These stages are prophase, prometaphase, metaphase, anaphase and telophase. During the process of mitosis the pairs of chromosomes condense and attach to fibers that pull the sister chromatids to opposite sides of the cell. The cell then divides in cytokinesis, to produce two identical daughter cells.[8] Because cytokinesis usually occurs in conjunction with mitosis, "mitosis" is often used interchangeably with "M phase". However, there are many cells where mitosis and cytokinesis occur separately, forming single cells with multiple nuclei. This occurs most notably among the fungi and slime moulds, but is found in various different groups. Even in animals, cytokinesis and mitosis may occur independently, for instance during certain stages of fruit fly embryonic development.[9] Errors in mitosis can either kill a cell through apoptosis or cause mutations that may lead to cancer.
Two key classes of regulatory molecules, cyclins and cyclin-dependent kinases (CDKs), determine a cell's progress through the cell cycle.[10] Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine for their discovery of these central molecules.[11] Many of the genes encoding cyclins and CDKs are conserved among all eukaryotes, but in general more complex organisms have more elaborate cell cycle control systems that incorporate more individual components. Many of the relevant genes were first identified by studying yeast, especially Saccharomyces cerevisiae;[12] genetic nomenclature in yeast dubs many these genes cdc (for "cell division cycle") followed by an identifying number, e.g., cdc25 or cdc20. Cyclins form the regulatory subunits and CDKs the catalytic subunits of an activated heterodimer; cyclins have no catalytic activity and CDKs are inactive in the absence of a partner cyclin. When activated by a bound cyclin, CDKs perform a common biochemical reaction called phosphorylation that activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle. Different cyclin-CDK combinations determine the downstream proteins targeted. CDKs are constitutively expressed in cells whereas cyclins are synthesised at specific stages of the cell cycle, in response to various molecular signals.[13] [edit] General mechanism of cyclin-CDK interaction This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (July 2010) Upon receiving a pro-mitotic extracellular signal, G1 cyclin-CDK complexes become active to prepare the cell for S phase, promoting the expression of transcription factors that in turn promote the expression of S cyclins and of enzymes required for DNA replication. The G1 cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for ubiquitination. Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the proteasome. Active S cyclin-CDK complexes phosphorylate proteins that make up the pre-replication complexes assembled during G1 phase on DNA replication origins. The phosphorylation serves two purposes: to activate each already-assembled pre-replication complex, and to prevent new complexes from forming. This ensures that every portion of the cell's genome will be replicated once and only once. The reason for prevention of gaps in replication is fairly clear, because daughter cells that are missing all or part of crucial genes will die. However, for reasons related to gene copy number effects, possession of extra copies of certain genes is also deleterious to the daughter cells. Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G2 phases, promote the initiation of mitosis by stimulating downstream proteins involved in chromosome condensation and mitotic spindle assembly. A critical complex activated during this process is a ubiquitin ligase known as the anaphase-promoting complex (APC), which promotes degradation of structural proteins associated with the chromosomal kinetochore. APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed. [edit] Specific action of cyclin-CDK complexes Cyclin D is the first cyclin produced in the cell cycle, in response to extracellular signals (e.g. growth factors). Cyclin D binds to existing CDK4, forming the active cyclin D-CDK4 complex. Cyclin D-CDK4 complex in turn phosphorylates the retinoblastoma susceptibility protein (Rb). The hyperphosphorylated Rb dissociates from the E2F/DP1/Rb complex (which was bound to the E2F responsive genes, effectively "blocking" them from transcription), activating E2F. Activation of E2F results in transcription of various genes like cyclin E,
cyclin A, DNA polymerase, thymidine kinase, etc. Cyclin E thus produced binds to CDK2, forming the cyclin E-CDK2 complex, which pushes the cell from G1 to S phase (G1/S transition). Cyclin B along with cdc2 (cdc2 - fission yeasts (CDK1 - mammalia)) forms the cyclin B-cdc2 complex, which initiates the G2/M transition.[14] Cyclin B-cdc2 complex activation causes breakdown of nuclear envelope and initiation of prophase, and subsequently, its deactivation causes the cell to exit mitosis.[13]
[edit] Inhibitors
Overview of signal transduction pathways involved in apoptosis, also known as "programmed cell death". Two families of genes, the cip/kip family (CDK interacting protein/Kinase inhibitory protein) and the INK4a/ARF (Inhibitor of Kinase 4/Alternative Reading Frame) prevent the progression of the cell cycle. Because these genes are instrumental in prevention of tumor formation, they are known as tumor suppressors. The cip/kip family includes the genes p21, p27 and p57. They halt cell cycle in G1 phase, by binding to, and inactivating, cyclin-CDK complexes. p21 is activated by p53 (which, in turn, is triggered by DNA damage e.g. due to radiation). p27 is activated by Transforming Growth Factor (TGF ), a growth inhibitor. The INK4a/ARF family includes p16INK4a, which binds to CDK4 and arrests the cell cycle in G1 phase, and p14arf which prevents p53 degradation. Synthetic inhibitors of Cdc25 could also be useful for the arrest of cell cycle and therefore be useful as antineoplastic and anticancer agents.[15]
with temporal expression patterns have allowed the identification of transcription factors that drive phase-specific gene expression.[16][20] The expression profiles of these transcription factors are driven by the transcription factors that peak in the prior phase, and computational models have shown that a CDK-autonomous network of these transcription factors is sufficient to produce steady-state oscillations in gene expression).[17][21] Experimental evidence also suggests that gene expression can oscillate with the period seen in dividing wild-type cells independently of the CDK machinery. Orlando et al. used microarrays to measure the expression of a set of 1,271 genes that they identified as periodic in both wild type cells and cells lacking all S-phase and mitotic cyclins (clb1,2,3,4,5,6). Of the 1,271 genes assayed, 882 continued to be expressed in the cyclin-deficient cells at the same time as in the wild type cells, despite the fact that the cyclin-deficient cells arrest at the border between G1 and S phase. However, 833 of the genes assayed changed behavior between the wild type and mutant cells, indicating that these genes are likely directly or indirectly regulated by the CDK-cyclin machinery. Some genes that continued to be expressed on time in the mutant cells were also expressed at different levels in the mutant and wild type cells. These findings suggest that while the transcriptional network may oscillate independently of the CDK-cyclin oscillator, they are coupled in a manner that requires both to ensure the proper timing of cell cycle events.[17] Other work indicates that phosphorylation, a post-translational modification, of cell cycle transcription factors by Cdk1 may alter the localization or activity of the transcription factors in order to tightly control timing of target genes (Ubersax et al. 2003; Sidorova et al. 1995; White et al. 2009).[19][22][23] While oscillatory transcription plays a key role in the progression of the yeast cell cycle, the CDK-cyclin machinery operates independently in the early embryonic cell cycle. Before the midblastula transition, zygotic transcription does not occur and all needed proteins, such as the B-type cyclins, are translated from maternally loaded mRNA.[24]
[edit] Checkpoints
Main article: Cell cycle checkpoint Cell cycle checkpoints are used by the cell to monitor and regulate the progress of the cell cycle.[25] Checkpoints prevent cell cycle progression at specific points, allowing verification of necessary phase processes and repair of DNA damage. The cell cannot proceed to the next phase until checkpoint requirements have been met. Several checkpoints are designed to ensure that damaged or incomplete DNA is not passed on to daughter cells. Two main checkpoints exist: the G1/S checkpoint and the G2/M checkpoint. G1/S transition is a rate-limiting step in the cell cycle and is also known as restriction point.[13] An alternative model of the cell cycle response to DNA damage has also been proposed, known as the postreplication checkpoint. p53 plays an important role in triggering the control mechanisms at both G1/S and G2/M checkpoints.
The cells which are actively undergoing cell cycle are targeted in cancer therapy as the DNA is relatively exposed during cell division and hence susceptible to damage by drugs or radiation. This fact is made use of in cancer treatment; by a process known as debulking, a significant mass of the tumor is removed which pushes a significant number of the remaining tumor cells from G0 to G1 phase (due to increased availability of nutrients, oxygen, growth factors etc.). Radiation or chemotherapy following the debulking procedure kills these cells which have newly entered the cell cycle.[13] The fastest cycling mammalian cells in culture, crypt cells in the intestinal epithelium, have a cycle time as short as 9 to 10 hours. Stem cells in resting mouse skin may have a cycle time of more than 200 hours. Most of this difference is due to the varying length of G1, the most variable phase of the cycle. M and S do not vary much. In general, cells are most radiosensitive in late M and G2 phases and most resistant in late S. For cells with a longer cell cycle time and a significantly long G1 phase, there is a second peak of resistance late in G1 The pattern of resistance and sensitivity correlates with the level of sulfhydryl compounds in the cell. Sulfhydryls are natural radioprotectors and tend to be at their highest levels in S and at their lowest near mitosis.
Cell cycle mathematical model Cell cycle analysis Mitosis Meiosis Interphase Autoradiography -- Used to determine the duration of each phase of the cell cycle. Biochemical Switches in the Cell Cycle Cdc25
[edit] References
1. ^ Cooper GM (2000). "Chapter 14: The Eukaryotic Cell Cycle". The cell: a
molecular approach (2nd ed.). Washington, D.C: ASM Press. ISBN 0-87893-106-6.
2. ^ Smith JA, Martin L (April 1973). "Do cells cycle?". Proc. Natl. Acad. Sci. U.S.A.
S-phase histone synthesis in dividing cells". Cell 27 (2 Pt 1): 32130. doi:10.1016/0092-8674(81)90415-3. PMID 7199388.
4. ^ Nelson DM, Ye X, Hall C, Santos H, Ma T, Kao GD, Yen TJ, Harper JW, Adams
independent of cyclin/cdk2 activity". Mol. Cell. Biol. 22 (21): 745972. doi:10.1128/MCB.22.21.7459-7472.2002. PMC 135676. PMID 12370293.
5. ^ Cameron IL, Greulich RC (July 1963). "Evidence for an essentially constant
duration of DNA synthesis in renewing epithelia of the adult mouse". J. Cell Biol. 18: 3140. doi:10.1083/jcb.18.1.31. PMC 2106275. PMID 14018040.
6. ^ Rubenstein, Irwin, and Susan M. Wick. "Cell." World Book Online Reference
David, Wright, Jill D (1997). Cells: Building Blocks of Life. New Jersey: Prentice Hall. pp. 704. ISBN 0-13423476-6.
9. ^ Lilly M, Duronio R (2005). "New insights into cell cycle control from the
Botstein D, Futcher B (December 1998). "Comprehensive identification of cell cycleregulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization". Mol. Biol. Cell 9 (12): 327397. PMC 25624. PMID 9843569.
13. ^ a b c d Robbins and Cotran; Kumar, Abbas, Fausto (2004). Pathological Basis of
Hanks, Steven. Protein kinase factsBook. Boston: Academic Press. pp. 184. ISBN 012-324719-5.
15. ^ Presentation on CDC25 PHOSPHATASES: A Potential Target for Novel
Anticancer Agents
16. ^ a b Pramila T, Wu W, Miles S, Breeden L (August 2006). "The Forkhead
transcription factor Hcm1 regulates chromosome segregation genes and fills the Sphase gap in the transcriptional circuitry of the cell cycle". Genes Dev 20 (20): 2266 227. doi:10.1101/gad.1450606. PMC 1553209. PMID 16912276.
17. ^ a b c Orlando DA, Lin CY, Bernard A, Wang JY, Socolar JES, Iversen ES,
Hartemink AJ, Haase SB (June 2008). "Global control of cell-cycle transcription by coupled CDK and network oscillators". Nature 453 (453): 944947. Bibcode 2008Natur.453..944O. doi:10.1038/nature06955.
18. ^ de Lichtenberg U, Jensen LJ, Fausbll A, Jensen TS, Bork P, Brunak S (April
2005). "Comparison of computational methods for the identification of cell cycleregulated genes". Bioinformatics 21 (7): 11641171. doi:10.1093/bioinformatics/bti093. PMID 15513999.
19. ^ a b White MA, Riles L, Cohen BA (February 2009). "A systematic screen for
transcriptional regulators of the yeast cell cycle". Genetics 181 (2): 43546. doi:10.1534/genetics.108.098145. PMC 2644938. PMID 19033152.
Saccharomyces cerevisiae". Science 298 (5594): 799804. Bibcode 2002Sci...298..799L. doi:10.1126/science.1075090. PMID 12399584.
21. ^ Simon I, et. al (September 2001). "Serial Regulation of Transcriptional Regulators
in the Yeast Cell Cycle". Cell 106 (6): 697708. doi:10.1016/S0092-8674(01)004949. PMID 11572776.
22. ^ Sidorova JM, Mikesell GE, Breeden LL (December 1995). "Cell cycle-regulated
phosphorylation of Swi6 controls its nuclear localization". Mol Biol Cell. 6 (12): 16411658. PMC 301322. PMID 8590795.
23. ^ Ubersax J, et. al (October 2003). "Targets of the cyclin-dependent kinase Cdk1".
"Cell cycle synchronization of porcine fetal fibroblasts: effects of serum deprivation and reversible cell cycle inhibitors". Biol. Reprod. 62 (2): 4129. doi:10.1095/biolreprod62.2.412. PMID 10642581.
27. ^ Pedrali-Noy G, Spadari S, Miller-Faurs A, Miller AO, Kruppa J, Koch G (January
1980). "Synchronization of HeLa cell cultures by inhibition of DNA polymerase alpha with aphidicolin". Nucleic Acids Res. 8 (2): 37787. doi:10.1093/nar/8.2.377. PMC 327273. PMID 6775308.
28. ^ Prather RS, Boquest AC, Day BN (1999). "Cell cycle analysis of cultured porcine
bovine embryos produced in vitro: effects of aphidicolin". Theriogenology 48 (6): 96976. doi:10.1016/S0093-691X(97)00323-3. PMID 16728186.
Morgan DO (2007). The Cell Cycle: Principles of Control. London: Published by New Science Press in association with Oxford University Press. ISBN 0-87893-5088. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2008). "Chapter 17". Molecular Biology of the Cell (5th ed.). New York: Garland Science. ISBN 978-08153-4111-6. Krieger M, Scott MP; Matsudaira PT, Lodish HF, Darnell JE, Zipursky L, Kaiser C; Berk A (2004). Molecular cell biology. New York: W.H. Freeman and CO. ISBN 07167-4366-3. Watson JD, Baker TA, Bell SP, Gann A, Levine M, Losick R (2004). "Chapter 7". Molecular biology of the gene (5th ed.). San Francisco: Pearson/Benjamin Cummings. ISBN 0-8053-4642-2.
This article incorporates public domain material from the NCBI document "Science Primer". Cell Cycle iBioSeminar by David Morgan (UCSF) Transcriptional program of the cell cycle: high-resolution timing Cell cycle and metabolic cycle regulated transcription in yeast Cell Cycle Animation 1Lec.com Cell Cycle and Cytokinesis - The Virtual Library of Biochemistry and Cell Biology Cell Cycle Cell Cycle Portal Fucci:Using GFP to visualize the cell-cycle Science Creative Quarterly's overview of the cell cycle Cells alive CCO The Cell-Cycle Ontology KEGG - Human Cell Cycle Cell cycle modeling Drosophila Cell Cycle Genes - The Interactive Fly [hide]v d eCell cycle proteins
Cyclin CDK
A (A1, A2) B (B1, B2, B3) D (D1, D2, D3) E (E1, E2) 2 3 4 5 6 7 8 9 10 CDK-activating kinase
CDK inhibitor INK4a/ARF (p14arf/p16, p15, p18, p19) cip/kip (p21, p27, p57) P53 p63 p73 family p53 p63 p73 Interphase M phase Phases and checkpoints Cell cycle checkpoints Other cellular phases G1 phase S phase G2 phase Mitosis (Preprophase Prophase Prometaphase Metaphase Anaphase Telophase) Cytokinesis Restriction point Spindle checkpoint Postreplication checkpoint Apoptosis G0 phase Meiosis
B bsyn: dna (repl, cycl, reco, repr) tscr (fact, tcrg, nucl, rnat, rept, ptts) tltn (risu, pttl, nexn) dnab, rnab/runp stru (domn, 1, 2, 3, 4) View page ratings Rate this page
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Progress in the eukaryotic cell cycle is driven by oscillations in the activities of CDKs (CyclinDependent Kinases). CDK activity is controlled by periodic synthesis and degradation of positive regulatory subunits, Cyclins, as well as by fluctuations in levels of negative regulators, by CKIs (CDK Inhibitors), and by reversible phosphorylation. The mammalian cell cycle consists of four discrete phases: S-phase, in which DNA is replicated; M-phase, in which the chromosomes are separated over
two new nuclei in the process of mitosis. These two phases are separated by two so called Gap phas G1 and G2, in which the cell prepares for the upcoming events of S and M, respectively (Ref.1). The different Cyclins, specific for the G1-, S-, or M-phases of the cell cycle, accumulate and activate CDK at the appropriate times during the cell cycle and then are degraded, causing kinase inactivation. Leve of some CKIs, which specifically inhibit certain Cyclin/CDK complexes, also rise and fall at specific times during the cell cycle (Ref.2). A breakdown in the regulation of this cycle leads to uncontrolled growth and contribute to tumor formation. Defects in many of the molecules that regulate the cell cyc also lead to tumor progression. Key among these are p53, the CKIs (p15 (INK4B), p16 (INK4A), p18 (INK4C), p19 (INK4D), p21, p27 (KIP1)), and Rb (Retinoblastoma Susceptibility Protein), all of whi act to keep the cell cycle from progressing until all repairs to damaged DNA have been completed.
In mammalian cells, different Cyclin-CDK complexes are involved in regulating different cell cycle transitions: Cyclin-D -CDK4/6 for G1 progression, Cyclin-E -CDK2 for the G1-S transition, Cyclin-A -CDK2 for S-phase progression, and Cyclin-A/B-CDC2 for entry into M-phase. Apart from these wel known roles in the cell cycle, several Cyclins and CDKs are involved in processes not directly related the cell cycle. Cyclin-D binds and activates the estrogen receptor. (Ref.6). The Cyclin-H -CDK7 complex is a component of both the CDK-activating kinase and the basal transcription factor TFIIH a can phosphorylate CDKs. Other Cyclins and CDKs (Cyclin-C-CDK8, Cyclin-T-CDK9, and Cyclin-K are also associated with RNA Polymerase-II and phosphorylate the carboxyl-terminal repeat domain. Cyclin-G, a target of p53, recruits PP2A (Protein Phosphatase 2A) to dephosphorylate MDM2 (Mous Double Minute 2) (Ref.3).
Cyclins associate with CDKs to regulate their activity and the progression of the cell cycle through specific checkpoints. Disruption of Cyclin action leads to either cell cycle arrest, or to uncontrolled ce cycle proliferation. Mitogenic signals that are received by cell surface receptors communicate to the nuclear cell cycle machinery to induce cell division through growth factor receptors that target Ras, which signals to a number of cytoplasmic signaling cascades such as PI3K (Phosphatidylinositiol3 Kinase), Raf and Rho. These proteins connect to the nuclear cell cycle machinery to mediate exit from Go into G1 and S-phase of the cell cycle. Activation of Ras leads to transcriptional induction of Cycli D1 in early G1 through a Ras-responsive element in the Cyclin-D1 gene promoter. Cyclin-D associate with CDK4 and CDK6 to form active Cyclin-D/CDK4 (or -6) complexes. This complex is responsibl for the first phosphorylation of tumor suppressor Rb in G1 (Ref.1). Subsequently, Cyclin-E is synthesized. When Cyclin-E is abundant it interacts with the cell cycle checkpoint kinase CDK2 and allow progression of the cell cycle from G1 to S-phase. One of the key targets of activated CDK2 complexed with Cyclin-E is Rb. When dephosphorylated in G1, Rb complexes with and blocks transcriptional activation by E2F transcription factors. But when CDK2/Cyclin-E phosphorylates Rb, dissociates from E2F, allowing E2F to activate the transcription of genes required for S-phase. E2F activity consists of a heterodimeric complex of an E2F polypeptide and a DP1 protein (Ref.5). One of the genes activated by E2F is Cyclin-E itself, leading to a positive feedback cycle as Cyclin-E accumulates. In S-phase, Cyclin-A is made, which in complex with DK2 adds further phosphates to R Cyclin-B is made in G2 and M-phases of the cell cycle (Ref.4). It combines with CDK1 (also called CDC2 or CDC28) to form the major mitotic kinase MPF (M-phase Promoting Factor). MPF causes entry of cells into mitosis and, after a lag, activates the system that degrades its Cyclin subunit. MPF inactivation, caused by the degradation of Cyclin-B, is required for exit from mitosis (Ref.2). 14-3-3s bind to the phosphorylated CDC2Cyclin-B kinase and exports it from the nucleus. During G2-phase CDC2 is maintained in an inactive state by the kinases Wee1 and Myt1 (Myelin Transcription Factor As cells approach M-phase, the phosphatase CDC25 is activated by PLK (Polo-Like Kinase). CDC25 then activates CDC2, establishing a feedback amplification loop that efficiently drives the cell into mitosis.
All Cyclins are degraded by ubiquitin-mediated processes, and the mode by which these systems are connected to the cell-cycle regulatory phosphorylation network, are different for mitotic and G1 Cycl
(Ref.2). The decision by the cell to either remain in G1 or progress into S-phase is the result in part of the balance between Cyclin-E production and proteolytic degradation in the proteosome. Cyclin-E is targeted for destruction by the proteosome through ubiquitination when associated with a complex of proteins called the SCF or F box complex. During G1-phase, the Rb-HDACs (Histone Deacetylases) repressor complex binds to the E2F-DP1 transcription factors, inhibiting the downstream transcription Many different stimuli exert checkpoint control including TGF-Beta, DNA damage, contact inhibition replicative senescence and growth factor withdrawal. The first four act by inducing members of the INK4A family or KIP/CIP families of cell cycle kinase inhibitors. TGF-Beta additionally inhibits the transcription of CDC25A, a phosphatase that activates the cell cycle kinases. DNA damage activates t DNA-PK/ATM/ATR kinases, initiating cascades that inactivate CDC2Cyclin-B.
Both synthesis and destruction of Cyclins are important for cell cycle progression. The destruction of Cyclin-B by Anaphase-Promoting Complex/cyclosome is essential for metaphase-anaphase transition and expression of indestructible Cyclin-B traps cells in mitosis (Ref.3). Cyclins-E and A have been implicated in the DNA replication initiation process in mammalian cells. In embryonic systems, Cycl E regulates replication in the absence of Cyclin-A. For centrosome duplication, in somatic cells Cycli A is required to induce DNA replication and it has also been implicated in activation of DNA synthes because of its appearance time relative to the onset time of DNA synthesis and its localization to sites nuclear DNA replication. Cyclin-E regulates the transcription of genes that encode the replication machinery but has also been implicated in the initiation process in mammalian cells (Ref.1). Similarly expression of indestructible Cyclin-A arrests cells in late mitosis. Overexpression of Cyclin-F also causes an accumulation of the G2/M (Ref.3). References:
1. Coqueret O
A study on the prognostic value of cyclins D1 and E expression levels in resectable gastric cancer and on some correlations between cyclins expression,histoclinical parameters and selected protein products of cell-cycle regulatory genes. J Exp Clin Cancer Res. 2005 Sep; 24(3):405-14.
3. Fung TK,Siu WY,Yam CH,Lau A,Poon RY.
Cyclin F is degraded during G2-M by mechanisms fundamentally different from other cyclins J Biol Chem. 2002 Sep 20; 277(38): 35140-9.
4. Coverley D,Laman H,Laskey RA.
Distinct roles for cyclins E and A during DNA replication complex assembly and activation. Nat Cell Biol. 2002 Jul; 4(7): 523-8.
5. Mundle SD,Saberwal G.
Involvement of G1/S cyclins in estrogen-independent proliferation of estrogen receptor-positiv breast cancer cells. Oncogene. 2002 Nov 21;21(53):8158-65
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quiescent) cells (Go) enter the cell division cycle at G1, the period when the cell grows and prepares for gression of the cell cycle requires that cell pass a restriction point in G1. Cells that do not pass through point re-enter Go. Cell cycles typically involve three additional phases, S, G2 and M. During S phase, sized and the centrosome is duplicated. During the M phase the cell divides (mitosis). G2 which follows he period when the cell prepares for mitosis.
e cyclin family of proteins are key regulators of the cell cycle. Cyclins bind and activate members of the nt kinase (Cdk) family to effect cell cycle progression. Cell cycle progression is controlled by the relative dual cyclin family members. Progression through the G1-S-G2-M cycle follows successive oscillations in clins, D, E, A and B.
uped into classes that relate to the phase of the cell cycle they regulate. Cyclin D family members are G1 hat regulate the entry of cells into G1 from Go. Cyclin D is upregulated by growth factor and external the Ras GTPase signaling pathway. Cyclin D couples with Cdk4 and Cdk6. The cyclin-D-dependent commitment to enter S-phase. Cyclin D-Cdk4 hypophosphorylates retinoblastoma protein (pRB) and xpression of cyclin E. Cyclin E and Cyclin A are able to bind Cdk2 and promote the cell cycle progression ransition. Cyclin E-Cdk2 and Cyclin A-Cdk2 hyperphosphorylate and inactivate pRb. The inactivation of tivation of E2F transcription factors. Cyclin E stimulates replication complex assembly through h Cdc6. Cyclin A activates DNA synthesis by the replication complex already assembled and inhibits w replication complex. Cyclin E reinitiates the replication complex that is blocked by cyclin A. Cyclins M-phase cyclins. Cyclin B1 and cyclin B2 and their catalytic partner, Cdk1 (cdc2, p34 kinase), are the M phase/maturation promoting (MPF) factor that regulates processes that lead to assembly of the and sister-chromatid pair alignment on the spindle. References: activation. Nat. Cell Biol. 4, 523-528.
1. Coverley, D. et. al. (2002) Distinct roles for cyclins E and A during DNA replication complex assemb
2. Keenan, S.M. et. al. (2004) Expression of cyclin E renders cyclin D-CDK4 dispensable for inactivatio
retinoblastoma tumor suppressor protein, activation of E2F, and G1-S phase progression. J. Biol. Che 5387-5396. phase. Genes Dev. 12, 2120-2130. M
4. Mateyak, M.K. et. al. (1999) c-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle
3. Leone, G. et. al. (1998) E2F3 activity is regulated during the cell cycle and is required for the inductio
at multiple independent points. Mol. Cell Biol. 19, 4672-4683. activation. Nat. Cell Biol. 4, 523-528.
1. Coverley, D. et. al. (2002) Distinct roles for cyclins E and A during DNA replication complex assemb
2. Keenan, S.M. et. al. (2004) Expression of cyclin E renders cyclin D-CDK4 dispensable for inactivatio
retinoblastoma tumor suppressor protein, activation of E2F, and G1-S phase progression. J. Biol. Che 5387-5396. phase. Genes Dev. 12, 2120-2130. M
3. Leone, G. et. al. (1998) E2F3 activity is regulated during the cell cycle and is required for the inductio
4. Mateyak, M.K. et. al. (1999) c-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle
Coverley, D. et. al. (2002) Distinct roles for cyclins E and A during DNA replication complex assembly and activation. Nat. Cell Biol. 4, 523-528. General mechanism of cyclin-CDK interaction. http://en.wikipedia.org/wiki/Cell_cycle. diakses tanggal 31 November 2011.pukul 20.30. Keenan, S.M. et. al. (2004) Expression of cyclin E renders cyclin D-CDK4 dispensable for inactivation of the retinoblastoma tumor suppressor protein, activation of E2F, and G1-S phase progression. J. Biol. Chem. 279, 5387-5396. Leone, G. et. al. (1998) E2F3 activity is regulated during the cell cycle and is required for the induction of S phase. Genes Dev. 12, 2120-2130. M Mateyak, M.K. et. al. (1999) c-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle progression at multiple independent points. Mol. Cell Biol. 19, 4672-4683.