’Restriction point control’ emlős sejtekben

Fluctuations of cyclins and p27 sup KIP1 during the cell cycle. Expression of cyclins E, A, and B (mitotic cyclin) is periodic. D-type cyclins are expressed throughout the cycle in response to mitogen stimulation (the period indicated by the top bar), and a less idealized scheme would indicate that different ones (D1, D2, and D3) are induced by various signals in a cell lineage-specific manner. The cyclins assemble with more stably expressed CDKs to temporally regulate their activities. D-type cyclins form complexes with CDK4 and CDK6; cyclin E with CDK2; cyclin A with CDK2 (in S phase) and with CDC2 (CDK1) (in late S and G sub 2); and cyclin B with CDC2. The holoenzymes can be negatively regulated by phosphorylation, so that even though cyclin B-CDC2 complexes progressively assemble as B cyclins accumulate, their catalytic activity is restricted to mitosis. p27 levels are high in quiescent cells, fall in response to mitogenic stimulation, remain at lower threshold levels in proliferating cells, and increase again when mitogens are withdrawn. In proliferating cells, most p27 is complexed with cyclin D-CDK complexes.

From:   Sherr: Science, Volume 274(5293).December 6, 1996.pp 1672-1677.

Restriction point control. RB phosphorylation triggered by cyclin D-dependent kinases releases RB-bound E2F. Rather than illustrating the many E2F-DP heterodimers that are differentially regulated by various RB family members, E2F "activity" is shown for simplicity. E2F triggers the expression of dihydrofolate reductase (DHFR), thymidine kinase (TK), thymidylate synthase (TS), DNA polymerase-alpha (POL), CDC2, cyclin E and possibly cyclin A, and E2F-1 itself. This establishes a positive feedback loop promoting RB phosphorylation by cyclin E-CDK2, contributing to the irreversibility of the restriction point transition and ultimately making it mitogen-independent. In parallel, cyclin E-CDK2 may oppose the inhibitory action of p27 sup KIP1 by phosphorylating it. This allows cyclin A-CDK2 and possibly cyclin E-CDK2 to start S phase. Possible CDK substrates include those of the origin-recognition complex (ORC), minichromosome maintenance proteins (MCMs), and CDC6, all of which assemble into preinitiation complexes. Once cells enter S phase, cyclin A-CDK2 phosphorylates DP-1 and inhibits E2F binding to DNA. Like p27, p53-inducible p21 sup CIP1 can induce G sub 1 arrest by inhibiting the cyclin D-, E-, and A-dependent kinases. In contrast, INK4 proteins antagonize only the cyclin D-dependent kinases. The proteins most frequently targeted in human cancers are highlighted. Arrows depicting inhibitory phosphorylations (P) or inactivating steps are shown in red, and those depicting activating steps are shown in black.