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Regulatory Cascade of Cyclin Gene Expression
When cells traverse the G0 to G1 phase to the S-phase transition, a series of cyclin-dependent kinases is activated. The addition of serum growth factors to quiescent cells promotes transcription of the cyclin D1 gene. Cyclin D1 then associates with pre-existing cdk4 to form an active complex. The kinase activity associated with this complex can phosphorylate specific sites on the retinoblastoma protein (pRb), leading to inactivation of pRb and the activation cyclin E transcription by E2F. Activation of the cyclin E gene can be blocked by the cdk inhibitor p16. Cyclin E associates with existing cdk2 and this active complex regulates the function of several sets of target proteins. First, cyclin E/cdk2 complexes associate with E2F/p107 complexes to activate expression of the cyclin A gene. Also, cyclin E/cdk2 complexes cooperate with cyclin D1 to amplify the phosphorylation of pRb. Cyclin A associates with cdk2 to form a kinase complex that phosphorylates downstream targets involved in the initiation of DNA replication.
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References:
Ohtani, K., Implication of transcription factor E2F in regulation of DNA replication. Front. Biosci., 4, D793-D804 (1999).
Lania, L., et al., Transcriptional control by cell-cycle regulators: a review. J. Cell. Physiol., 179, 134-141 (1999).
Hatakeyama, M., et al., The role of RB in cell cycle control. Prog. Cell Cycle Res., 1, 9-19 (1995).
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