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cell cycle

Sunday 13 July 2003

The cell cycle is required for cell growth and cell division into two daughter cells. A eukaryotic cell cannot divide unless it replicates its genome (DNA) and then separates the duplicated genome. To achieve these tasks cells must perform DNA synthesis and mitosis.

The cell cycle is an ordered set of events. The G1 phase stands for "GAP-1" and is required for cell growth and preparation of DNA synthesis. The S-phase stands for "Synthesis" and replicates the genome. The G2 phase is "GAP-2" and needed for cell growth and preparation for mitosis. The last phase is M and it stands for "Mitosis" in which cells segregate duplicated chromosomes.

Steps

- G1 phase
- S phase
- G2 phase
- M phase (mitosis)

Regulation of the cell cycle

Resting (nondividing) cells are in the G0 stage of the cell cycle and need to be recruited into the G1 stage and beyond in order to undergo replication.

The orderly progression of cells through the various phases of cell cycle is orchestrated by cyclins and cyclin-dependent kinases (CDKs), and by their inhibitors.

CDKs drive the cell cycle by phosphorylating critical target proteins that are required for progression of the cells to the next phase of the cell cycle.

CDKs are expressed constitutively during the cell cycle but in an inactive form. They are activated by phosphorylation after binding to the family of proteins called cyclins.

By contrast with CDKs, cyclins are synthesized during specific phases of the cell cycle, and their function is to activate the CDKs. On completion of this task, cyclin levels decline rapidly.

More than 15 cyclins have been identified; cyclins D, E, A, and B appear sequentially during the cell cycle and bind to one or more CDKs.

The human cell cycle is regulated by the interaction of multiple proteins, including cyclins (CCNs), cyclin-dependent kinases (CDKs) and phosphatases. Complexes containing CDKs, cyclins (CCNs), proliferating cell nuclear antigen (PCNA), and several other proteins regulate the major cell cycle transition points at the G1/S and G2/M boundaries. In addition to CDKN1A (p21) and PCNA, the CDK2/CCNAs kinase complex includes SKP1 (p19) and SKP2 (p45).

Cyclin-D and RB Phosphorylation

Cyclin-D, the first cyclin to increase in the cell cycle, appears in mid G1 but is no longer detectable in the S phase. There are three forms of cyclin-D, named cyclin-D1, cyclin-D2, and cyclin-D3, but to simplify matters, we will use the general term "cyclin-D." Cyclin-D, like other cyclins, is unstable and is degraded through the ubiquitin-proteasome pathway.

During the G1 phase of the cell cycle, cyclin D binds to and activates CDK4, forming a cyclin D-CDK4 complex. This complex has a critical role in the cell cycle by phosphorylating the retinoblastoma susceptibility protein (RB).

The phosphorylation of RB is a molecular ON-OFF switch for the cell cycle. In its hypophosphorylated state, RB prevents cells from replicating by forming a tight, inactive complex with the transcription factor E2F. (E2F is a family of transcription factors, referred to here as "E2F.")

Phosphorylation of RB dissociates the complex and releases the inhibition on E2F transcriptional activity. Thus phosphorylation of RB eliminates the main barrier to cell-cycle progression and promotes cell replication.

Hypophosphorylated RB, present in quiescent cells (in G0 or early G1), binds to a protein complex that contains E2F and a subunit called DP1. The E2F/DP1/RB complex binds to promoters of E2F-responsive genes.

Bound to the E2F/DP1/RB complex, such genes are silent because RB recruits histone deacetylase, an enzyme that causes compaction of chromatin and inhibition of transcription.

When quiescent cells are stimulated by growth factors, the concentrations of cyclin-D and cyclin-E go up, resulting in the activation of cyclin D-CDK4 and cyclin E-CDK2 at the G1/S restriction point and causing phosphorylation of RB.

Hyperphosphorylated RB dissociates from the complex, activating the transcription of E2F target genes that are essential for progression through the S phase.

These include cyclin E, DNA polymerases, thymidine kinase, dihydrofolate reductase, and several others.

During the M phase (mitosis), the phosphate groups are removed from RB by cellular phosphatases, thus regenerating the hypophosphorylated form of RB.

Cell-Cycle Progression Beyond the G1/S Restriction Point

Further progression through the S phase and the initiation of DNA replication involve the formation of an active complex between cyclin-E and CDK2.

Activated E2F increases the transcription of cyclin E and of polymerases needed for DNA replication, thus stimulating DNA synthesis.

The next decision point in the cell cycle is the G2/M transition. This transition is initiated by the E2F-mediated transcription of cyclin A, which forms the cyclin A-CDK2 complex that regulates events at the mitotic prophase.

The main mediator that propels the cell beyond prophase is the cyclin B-CDK1 complex, which is activated by a protein phosphatase (Cdc 25) and begins to accumulate in the nucleus in early prophase.

Cyclin B-CDK1 activation causes the breakdown of the nuclear envelope and initiates mitosis.

Complexes of CDKs with cyclins A (there are two cyclin A isoforms, A1 and A2; A2 is essential for the cell cycle) and B regulate some critical events at the G2/M transition, such as the decrease in microtubule stability, the separation of centrosomes, and chromosome condensation.

Exit from mitosis requires the inactivation of cyclin B-CDK1. Newly divided cells can then return to G1 and initiate a new replicative cycle or go into quiescence.

In proliferating cells, cyclin E-CDK2 may be replaced in some of its functions by a complex between cyclin A2 and CDK1. However, the absence of both isoforms of cyclin E (E1 and E2) prevent quiescent cells from entering the cell cycle.

See also

- cell-cycle inhibitors
- cell-cycle checkpoints (cellular cycle checkpoints)
- cellular cycle arrest
- cellular cycle checkpoint kinases

Pathology

- Cell cycle regulation and cancer

References

- Branzei D, Foiani M. Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol. 2008 Apr;9(4):297-308. PMID: 18285803

- Coller HA. What’s taking so long? S-phase entry from quiescence versus proliferation. Nat Rev Mol Cell Biol. 2007 Aug;8(8):667-70. PMID: 17637736

- Sluder G. Two-way traffic: centrosomes and the cell cycle. Nat Rev Mol Cell Biol. 2005 Sep;6(9):743-8. PMID: 16231423

- Senderowicz AM. Targeting cell cycle and apoptosis for the treatment of human malignancies. Curr Opin Cell Biol. 2004 Dec;16(6):670-8. PMID: 15530779

- Harper JW. A phosphorylation-driven ubiquitination switch for cell-cycle control. Trends Cell Biol. 2002 Mar;12(3):104-7. PMID: 11859016


- Cell cycle regulation and cancer by R. Bernards (ESGM)