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 Cyclins and Cell Cycle Regulation

Non-dividing (quiescent) cells (Go) enter the cell division cycle at G1, the period when the cell grows and prepares for replication. Progression of the cell cycle requires that cell pass a restriction point in G1. Cells that do not pass through this restriction point re-enter Go. Cell cycles typically involve three additional phases, S, G2 and M. During S phase, DNA is synthesized and the centrosome is duplicated. During the M phase the cell divides (mitosis). G2 which follows the S phase is the period when the cell prepares for mitosis.

Members of the cyclin family of proteins are key regulators of the cell cycle. Cyclins bind and activate members of the cyclin-dependent kinase (Cdk) family to effect cell cycle progression. Cell cycle progression is controlled by the relative levels of individual cyclin family members. Progression through the G1-S-G2-M cycle follows successive oscillations in the levels of cyclins, D, E, A and B.

Cyclins are grouped into classes that relate to the phase of the cell cycle they regulate. Cyclin D family members are G1 phase cyclins that regulate the entry of cells into G1 from Go. Cyclin D is upregulated by growth factor and external signals through the Ras GTPase signaling pathway. Cyclin D couples with Cdk4 and Cdk6. The cyclin-D-dependent kinases enforce commitment to enter S-phase. Cyclin D-Cdk4 hypophosphorylates retinoblastoma protein (pRB) and facilitates the expression of cyclin E. Cyclin E and Cyclin A are able to bind Cdk2 and promote the cell cycle progression through G1/S transition. Cyclin E-Cdk2 and Cyclin A-Cdk2 hyperphosphorylate and inactivate pRb. The inactivation of pRb leads to activation of E2F transcription factors. Cyclin E stimulates replication complex assembly through interaction with Cdc6. Cyclin A activates DNA synthesis by the replication complex already assembled and inhibits assembly of new replication complex. Cyclin E reinitiates the replication complex that is blocked by cyclin A. Cyclins B1 and B2 are M-phase cyclins. Cyclin B1 and cyclin B2 and their catalytic partner, Cdk1 (cdc2, p34 kinase), are components of the M phase/maturation promoting (MPF) factor that regulates processes that lead to assembly of the mitotic spindle and sister-chromatid pair alignment on the spindle.