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Cyclins and Cell Cycle Regulation | GeneGlobe

Cyclins and Cell Cycle Regulation

Pathway

Pathway Description

Progression through the eukaryotic cell cycle is driven by oscillations in the activities of Cyclin-dependent kinases (CDK). CDK activity is controlled by periodic synthesis and degradation of positive regulatory subunits named cyclins, as well as by fluctuations in levels of negative regulators named CDK inhibitors (CKI). 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' phases named G1 and G2, in which the cell prepares for the upcoming events of S phase and M phase, respectively. Different cyclins specific for G1, S, or M phases of the cell cycle accumulate and activate CDKs at appropriate times during the cell cycle, and are then degraded causing kinase inactivation. Levels of some CKIs which specifically inhibit cyclin/CDK complexes also rise and fall at specific times during the cell cycle. A breakdown in the regulation of this cycle leads to uncontrolled growth and contributes to tumor formation. Defects in many of the molecules that regulate the cell cycle also lead to tumor progression. Key among these are p53, the CKIs (p15INK4B, p16INK4A, p18INK4C, p19INK4D, p21, p27KIP1) and Rb.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. Mitogenic signals that are received by cell surface receptors communicate to the nuclear cell cycle machinery to induce cell division. For example, growth factors induce the transcriptional activation of Cyclin D genes in early G1. Cyclin D proteins associate with CDK4 or CDK6 to form active Cyclin D-CDK4/6 complexes. This complex is responsible for the first phosphorylation of tumor suppressor Rb in G1. Subsequently, Cyclin E is synthesized. When Cyclin E is abundant, it interacts with the cell cycle checkpoint kinase CDK2 and allows 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. On phosphorylation, Rb dissociates from E2F which allows E2F to activate the transcription of genes required for S phase. In S phase, Cyclin A is synthesized, which in complex with CDK2 further phosphorylates Rb. Cyclin B is made in G2 and M phases of the cell cycle. It combines with CDC2 to form the major mitotic kinase MPF. 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. 14-3-3 proteins bind to phosphorylated CDC2-Cyclin B kinase and export it from the nucleus. During G2 phase, CDC2 is maintained in an inactive state by the kinases Wee1 and Myt1. As cells approach M phase, the phosphatase CDC25 is activated and goes on to activate 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 cyclins. The decision by the cell to either remain in G1 or progress into S phase is in part the result of the balance between Cyclin E production and proteasomal degradation. Many different stimuli exert checkpoint control, including TGF-β, 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-β additionally inhibits the transcription of CDC25A.