cell-cycle inhibitors

The activity of cyclin-CDK complexes is tightly regulated by inhibitors, called CDK inhibitors. These inhibitors function as tumor suppressors and are frequently altered in tumors.

There are two main classes of CDK inhibitors: the Cip/Kip and the INK4/ARF families.

Cip/Kip family

The Cip/Kip family has three components, p21, p27, and p57, which bind to and inactivate the complexes formed between cyclins and CDKs.

Transcriptional activation of p21 is under the control of p53, encoded by the tumor suppressor gene TP53 that is mutated in a large proportion of human cancers. The main role of p53 in the cell cycle is one of surveillance, triggering checkpoint controls that slow down or stop cell-cycle progression of damaged cells, or causes apoptosis.

INK4/ARF families

The human INK4a/ARF locus (a notation for "inhibitor of k inase 4/a lternative reading frame") encodes two proteins, p16INK4a and p14ARF, which block the cell cycle and act as tumor suppressors.

p16INK4a competes with cyclin D for binding to CDK4 and inhibits the ability of the cyclin D-CDK4 complex to phosphorylate RB, thus causing cell-cycle arrest at late G1. It is frequently mutated or inactivated by hypermethylation in human cancers.

The INK4a locus encodes a second gene product, p14ARF (p19ARF in mice), which acts on p53 (TP53). p14ARF arises from an alternative reading of the INK4a gene.

Although both p16INK4a and p14ARF block the cell cycle, their targets are different; p16INK4a acts on cyclin D-CDK4, whereas p14ARF prevents p53 degradation.

See also

 cell cycle
 cyclins (CCNs)
 CDKs