Cell cycle
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2008-07-16T19:18:34Z
206.83.48.4
/* M phase */
The '''cell cycle''', or '''cell-division cycle''', is the series of events that take place in a [[eukaryote|eukaryotic]] [[cell (biology)|cell]] leading to its replication. These events can be divided in two brief periods: [[interphase]]—during which the cell grows, accumulating nutrients needed for mitosis and [[DNA replication|duplicating its DNA]]—and the [[mitosis|mitotic]] (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 cell]]s, and some internal organs are renewed.
==Phases of the cell cycle==
[[image:Cell Cycle 2.png|thumb|300px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=[[Mitosis]], G<sub>1</sub>=[[G1 phase|Gap 1]], G<sub>2</sub>=[[G2 phase|Gap 2]], S=[[S phase|Synthesis]]; not in ring: G<sub>0</sub>=[[G0 phase|Gap 0/Resting]]. The duration of mitosis in relation to the other phases has been exaggerated in this diagram.]]
The cell cycle consists of four distinct phases: [[G1 phase|G<sub>1</sub> phase]], [[S phase]], [[G2 phase|G<sub>2</sub> phase]] (collectively known as interphase) and [[M phase]]. 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 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|G<sub>0</sub> phase]].
===M phase===
The relatively brief [[M phase]] consists of nuclear division ([[karyokinesis]]) and [[cytoplasm]]ic division ([[cytokinesis]]). In [[plant]]s and [[alga]]e, cytokinesis is accompanied by the formation of a new [[cell wall]].
===Interphase===
After M phase, the daughter cells each begin [[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.
====G<sub>1</sub> phase====
The first phase within interphase, from the end of the previous M phase till the beginning of DNA synthesis is called [[G1 phase|G<sub>1</sub>]] (G indicating ''gap'' or ''growth''). 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 G<sub>1</sub> is highly variable, even among different cells of the same species.<ref>{{cite journal | url=http://www.pnas.org/cgi/reprint/70/4/1263 | title=Do Cells Cycle? |author=J. A. Smith and L. Martin | journal= PNAS | date= April 1, 1973 | volume= 70 | issue= 4 |pages= 1263-1267 | pmid = 4515625 | doi = 10.1073/pnas.70.4.1263 }} </ref>
====S phase====
The ensuing [[S phase]] starts when [[DNA]] synthesis commences; when it is complete, all of the [[chromosome]]s 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. An exception to this is [[histone]] production, most of which occurs during the S phase.<ref>{{cite journal | url=http://www.cell.com/content/article/abstract?uid=PII0092867481904153 | title=Separation of basal histone synthesis from S-phase histone synthesis in dividing cells | journal= Cell| volume=27| pages=321-330 | date=December 1981 | pmid = 7199388 | doi = 10.1016/0092-8674(81)90415-3 }}</ref><ref>{{cite journal | url=http://mcb.asm.org/cgi/content/abstract/22/21/7459 | title=Coupling of DNA Synthesis and Histone Synthesis in S Phase Independent of Cyclin/cdk2 Activity| journal= Molecular and Cellular Biology| date= November 2002 | pages=7459-7472| volume=22| issue=21 | pmid = 12370293 | doi = 10.1128/MCB.22.21.7459-7472.2002 }}</ref> The duration of S phase is relatively constant among cells of the same species.<ref> {{cite journal | url=http://www.jcb.org/cgi/content/abstract/18/1/31 | title=Evidence for an essentially constant duration of dna synthesis in renewing epithelia of the adult mouse | author= Ivan L. Cameron and Richard C. Greulich | journal= Journal of Cell Biology | volume=18 | pages= 31-40 | pmid = 14018040 | doi = 10.1083/jcb.18.1.31 }}</ref>
====G<sub>2</sub> phase====
The cell then enters the [[G2 phase|G<sub>2</sub> phase]], which lasts until the cell enters mitosis. Again, significant protein synthesis occurs during this phase, mainly involving the production of [[microtubule]]s, which are required during the process of mitosis. Inhibition of protein synthesis during G<sub>2</sub> phase prevents the cell from undergoing mitosis.
===G<sub>0</sub> phase===
The term "post-mitotic" is sometimes used to refer to both [[G0 phase|quiescent]] and [[Senescence#Cellular senescence|senescent]] cells. Nonproliferative cells in multicellular [[eukaryote]]s generally enter the quiescent G<sub>0</sub> state from G<sub>1</sub> and may remain quiescent for long periods of time, possibly indefinitely (as is often the case for [[neuron]]s). This is very common for cells that are fully [[cellular differentiation|differentiated]]. Cellular senescence is a state that occurs in response to DNA damage or degradation that would make a cell's progeny nonviable; it is often a biochemical alternative to the self-destruction of such a damaged cell by [[apoptosis]]. Some cell types in mature organisms, such as [[parenchymal]] cells of the liver and kidney, enter the G<sub>0</sub> phase semi-permanently and can only be induced to begin dividing again under very specific circumstances; other types, such as [[epithelial cell]]s, continue to divide throughout an organism's life.
==Regulation of cell cycle==
[[Image:Regulation of cell cycle.png|thumb|200px|Regulation of cell cycle: Schematic]]
Regulation of the cell cycle involves steps crucial to the cell, including detecting and repairing genetic damage, and provision of various checks to prevent uncontrolled cell division. The molecular events that control the cell cycle are ordered and directional; that is, each process occurs in a sequential fashion and it is impossible to "reverse" the cycle.
===Role of Cyclins and CDKs===
Two key classes of regulatory molecules, [[cyclin]]s and [[cyclin-dependent kinase]]s (CDKs), determine a cell's progress through the cell cycle.<ref>{{cite journal | url= http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=7575488&dopt=Citation | title=Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle | journal=Bioessays | date=1995 Jun | volume=17| issue=6| pages=471-80 | pmid = 7575488 | doi = 10.1002/bies.950170603 }}</ref> [[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.<ref> {{cite web| url=http://nobelprize.org/nobel_prizes/medicine/laureates/2001/press.html | publisher=Nobelprize.org | title=Press release}}</ref> Many of the genes encoding cyclins and CDKs are [[conservation (genetics)|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]]'';<ref>{{cite journal | url=http://www.molbiolcell.org/cgi/content/abstract/9/12/3273 | title=Comprehensive Identification of Cell Cycle-regulated Genes of the Yeast Saccharomyces cerevisiae by Microarray Hybridization | journal=Molecular Biology of the Cell | volume=9 | pages=3273-3297 | date= December 1998 | pmid = 9843569 }}</ref> genetic nomenclature in yeast dubs many of these genes ''cdc'' (for "cell division cycle") followed by an identifying number, e.g., ''[[cdc25]]''.
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.<ref name="Robbins"> {{cite book |last= Robbins and Cotran |coauthors= Kumar, Abbas, Fausto |title= Pathological Basis of Disease |publisher= [[Elsevier]] |year= 2004 |isbn= 81-8147-528-3 }} </ref>
====General mechanism of cyclin-CDK interaction====
Upon receiving a pro-mitotic extracellular signal, G<sub>1</sub> [[cyclin-CDK]] complexes become active to prepare the cell for S phase, promoting the expression of [[transcription factor]]s that in turn promote the expression of S cyclins and of enzymes required for [[DNA replication]]. The G<sub>1</sub> 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 complex]]es assembled during G<sub>1</sub> phase on DNA [[origin of replication|replication origin]]s. 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 would also prove deleterious to the daughter cells.
Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G<sub>2</sub> 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.
====Specific action of cyclin-CDK complexes====
[[Cyclin D]] is the first cyclin produced in the cell cycle, in response to extracellular signals (eg. [[growth factor]]s). Cyclin D binds to existing [[Cyclin-dependent kinase 4|CDK4]], forming the active cyclin D-CDK4 complex. Cyclin D-CDK4 complex in turn phosphorylates the [[retinoblastoma]] susceptibility protein ([[Retinoblastoma 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 [[Cyclin-dependent kinase 2|CDK2]], forming the cyclin E-CDK2 complex, which pushes the cell from G<sub>1</sub> to S phase (G<sub>1</sub>/S transition). Cyclin A along with CDK2 forms the cyclin A-CDK2 complex, which initiates the G<sub>2</sub>/M transition. [[Cyclin B]]-CDK1 complex activation causes breakdown of [[nuclear envelope]] and initiation of [[prophase]], and subsequently, its deactivation causes the cell to exit mitosis.<ref name="Robbins"/>
===Cell cycle inhibitors===
Two families of genes, the ''cip/kip'' family and the INK4a/ARF (''In''hibitor of ''K''inase 4/''A''lternative ''R''eading ''F''rame) prevent the progression of the cell cycle. Because these genes are instrumental in prevention of [[tumor]] formation, they are known as [[tumor suppressor]]s.
The '''''cip/kip'' family''' includes the genes [[p21]], [[p27 (gene)|p27]] and [[P57 (gene)|p57]]. They halt cell cycle in G<sub>1</sub> phase, by binding to, and inactivating, cyclin-CDK complexes. p21 is activated by [[p53]] (which, in turn, is triggered by DNA damage eg. due to radiation). p27 is activated by Transforming Growth Factor β ([[TGF β]]), a growth inhibitor.
The '''INK4a/ARF family''' includes [[p16INK4a]], which binds to CDK4 and arrests the cell cycle in G<sub>1</sub> phase, and [[p14arf]] which prevents p53 degradation. And the amount of chromosomes are able to double at the same rate as in phase 2
==Checkpoints==
[[Cell cycle checkpoint]]s are used by the cell to monitor and regulate the progress of the cell cycle.<ref>{{cite journal | url=http://www.sciencemag.org/cgi/content/abstract/274/5293/1664 | title= Cell Cycle Checkpoints: Preventing an Identity Crisis| author= Stephen J. Elledge| journal= Science | date= 6 December 1996 | volume=274 | issue=5293| pages= 1664-1672 | pmid = 8939848 | doi = 10.1126/science.274.5293.1664 }}</ref> 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 [[Cell_cycle_checkpoint#Restriction_Checkpoint|G1/S checkpoint]] and the [[Cell cycle checkpoint#G2 Checkpoint|G2/M checkpoint]]. G1/S transition is a rate-limiting step in the cell cycle and is also known as [[restriction point]].<ref name="Robbins"/> 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.
== Role of cell cycle in tumor formation ==
A disregulation of the cell cycle components may lead to [[tumor]] formation. As mentioned above, some genes like the cell cycle inhibitors, [[RB]], [[p53]] etc., when they mutate, may cause the cell to multiply uncontrollably, forming a tumor. Although the duration of cell cycle in tumor cells is equal to or longer than that of normal cell cycle, the proportion of cells that are in active cell division (versus quiescent cells in G0 phase) in tumor cells are much more compared to that in normal cells. Thus there is a net increase in cell number as the number of cells that die by apoptosis or senescence remains the same.
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 [[Chemotherapy|drugs]] or [[Radiotherapy|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. <ref name="Robbins"/>
==Synchronization of cell cultures==
Several methods can be used to [[Cell synchronization|synchronise cell cultures]] by halting the cell cycle at a particular phase. For example, [[Serum starvation]] <ref>{{cite journal | url=http://www.biolreprod.org/cgi/content/abstract/62/2/412 | title=Cell Cycle Synchronization of Porcine Fetal Fibroblasts: Effects of Serum Deprivation and Reversible Cell Cycle Inhibitors | journal= Biology of Reproduction | volume=62 | pages=412-419 | year=2000 | pmid = 10642581 | doi = 10.1095/biolreprod62.2.412 }}</ref> and treatment with [[Thymidine]] or [[Aphidicolin]] <ref>{{cite journal | url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=327273 | title=Synchronization of HeLa cell cultures by inhibition of DNA polymerase alpha with aphidicolin| author= G Pedrali-Noy, S Spadari, A Miller-Faurès, A O Miller, J Kruppa, and G Koch | journal=Nucleic Acids Res | date= 1980 January 25; | volume=8| issue=2 | pages=377–387 | pmid = 6775308 | doi = 10.1093/nar/8.2.377 }}</ref> halt the cell in the G1 phase, [[Mitotic shake-off]], treatment with [[colchicine]] <ref>{{cite journal | url=http://www.liebertonline.com/doi/abs/10.1089/15204559950020067?cookieSet=1&journalCode=clo | title=Cell Cycle Analysis of Cultured Porcine Mammary Cells | author= R.S. Prather, A.C. Boquest, B.N. Day| journal= Cloning| year= 1999 | volume= 1| issue=1| pages=17-24 | pmid = 16218827 | doi = 10.1089/15204559950020067 }}</ref> and treatment with [[Nocodazole]] <ref> {{cite journal | title= Synchronization of cell division in eight-cell bovine embryos produced in vitro: Effects of nocodazole | author=Seydou Samaké, Lawrence C. Smith | journal=Theriogenology | date=1997 Oct 15| volume=48| issue=6|pages=969-76 | pmid = 16728186 | doi = 10.1016/S0093-691X(97)00323-3 }}</ref> halt the cell in M phase and treatment with [[5-fluorodeoxyuridine]] halts the cell in S phase.
==Observation==
There are numerous ways to observe the cell cycle occurring. Onion bulbs or garlic root tips are often used.
A sample of root tip is fixed in a mixture of 99% of 70% aqueous industrial methylated spirit and 1% glacial [[ethanoic acid]] for two hours. Treat the root tips in 1 [[Concentration#Molarity|molar]] [[hydrochloric acid]] at 60°C for 6–7 minutes. Rinse thoroughly with water. Add [[Schiff's reagent]] and leave for one hour. Rinse again in distilled water. Observe under a microscope.
== Mathematical modelling==
''See [[Mathematical biology#Example of a model: The Cell Cycle|cell cycle mathematical model]]''
== See also ==
*[[List of basic cell biology topics]]
*[[Mitosis]]
*[[Interphase]]
==References==
{{reflist|2}}
# Morgan DO. (2007) ''The Cell Cycle: Principles of Control''. New Science Press: London.
# Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. (2003). ''Molecular Biology of the Cell''. Ch 17. Garland Science: New York. 4th ed.
# Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J. (2004). ''Molecular Cell Biology''. WH Freeman: New York, NY. 5th ed.
# Watson JD, Baker TA, Bell SP, Gann A, Levine M, Losick R. (2004). ''Molecular Biology of the Gene'', Ch. 7. Peason Benjamin Cummings; CSHL Press. 5th ed.
==External links==
* {{NCBI-scienceprimer}}
* [http://www.cellcycle.info Transcriptional program of the cell cycle: high-resolution timing]
* [http://www.sceptrans.org Cell cycle and metabolic cycle regulated transcription in yeast]
* [http://www.biochemweb.org/cell_cycle.shtml Cell Cycle and Cytokinesis - The Virtual Library of Biochemistry and Cell Biology]
* [http://www.landesbioscience.com/journals/cc/index.php Cell Cycle]
* [http://www.cellcycles.org Cell Cycle Portal]
* [http://www.conncoll.edu/ccacad/zimmer/GFP-ww/cooluses19.html Fucci:Using GFP to visualize the cell-cycle]
* [http://www.scq.ubc.ca/?p=248 Science Creative Quarterly's overview of the cell cycle]
* [http://www.cellsalive.com Cells alive]
* [http://www.cellcycleontology.org CCO] The Cell-Cycle Ontology
* [http://www.genome.ad.jp/kegg/pathway/hsa/hsa04110.html KEGG - Human Cell Cycle]
* [http://mpf.biol.vt.edu/Research.html Cell cycle modeling]
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