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Background

Eukaryotic cell cycle progression is dependent, in part, on the tightly regulated activity of cyclin dependent kinases (CDKs). Cyclin D/CDK4/6 activity occurs in mid-late G1 phase, upstream of CDK2/cyclin E activity.

Cyclin D is degraded through the ubiquitin proteasome pathway in the absence of mitogenic signaling. p27/Kip1, p57 Kip2 and p21 Waf1/Cip1 are members of the Cip/Kip family of cyclin-dependent kinase inhibitors. They form heterotrimeric complexes with cyclins and CDKs, inhibiting kinase activity and blocking progression through G1/S phase .

Levels of p27 are upregulated in quiescent cells and in cells treated with negative cell cycle regulators. p27 nuclear localization is controlled by Akt-dependent phosphorylation at Thr157. The inhibitors of CDK4 (INK4) family include p15 INK4B, p16 INK4A, p18 INK4C, and p19 INK4D. All INK4 proteins selectively inhibit CDK4/6 activity, either in a binary complex, or in a ternary complex including cyclin D, resulting in inhibition of cell division.