Growth factor-regulated G1 cyclins.

Abstract

Mammalian D-type cyclins act as regulatory subunits of cyclin-dependent kinases (cdks) to form holoenzymes whose activities are both necessary and rate limiting for progression through the first gap phase (G1) of the cell cycle. D-type cyclins act as growth factor sensors to integrate receptor-mediated signals with the cell cycle machinery and to thereby enforce the decision of cells to enter their DNA synthetic (S) phase. Mitogenic and anti-proliferative stimuli affect the transcription of D-type cyclin genes and modulate both cyclin and cdk protein synthesis, their assembly into holoenzymes, post-translational modification, and serine/threonine kinase activity. In turn, the holoenzymes facilitate G1 exit by phosphorylating key cellular substrates, the retinoblastoma protein among them. Negative regulators of macrophage G1 progression, including cyclic AMP and the immunosuppressant rapamycin, extinguish the activity of G1 cyclin-dependent kinases by inducing novel polypeptide inhibitors that both inhibit the post-translational activation of cyclin-bound cdks and directly interfere with their catalytic functions. Our emerging understanding of G1 cyclins, their associated cdks, their proximal regulators, and their cdk substrates has now begun to provide a mechanistic understanding of how cells interpret mitogenic signals and make the decision to replicate their chromosomal DNA.