CKIs cyclin-dependent kinase inhibitors

Negative control of CDK activity in the cell cycle is performed by specific inhibitor proteins known as cyclin-dependent kinase inhibitors, CKIs (review Morgan, 1995 Pines, 1995 Peter, 1997). These are a heterogenous family of proteins that may associate with a CDK or with a CDK-cyclin complex in a reversible maimer, inhibiting CDK activity. 

Peter, M. The regulation of cyclin-dependent kinase inhibitors (CKIs) (1997) Prog CeU Cycle Res 3, 99-108... 

Cellular proliferation is controlled by the cell cycle, which is governed by the cyclical activation of the cyclin-dependent kinase (cdk) complexes [cyclin-endogenous cdk inhibitors (CKIs)]. A dysregulated cell cycle due to overexpression of cyclins and cdks, and inactivation of the retinoblastoma (Rb) and the p53 tumor suppressor proteins, is a hallmark of cancer. Any agent downregulating cyclins or cdks will result in cell cycle arrest that can occur either at Gi/S or G2/M phase, an irreversible process that will ultimately lead to cell apoptosis. 

The hyper-proliferation of tumor is a highly regulated process that progresses like normal cells through the four phases of cell cycle - Gl, S, G2, and M - which are controlled by cell cycle regulatory proteins. These include cyclins (cyclin A, B, Ds, or E), cyclin-dependent kinase (CDK CDKl, 2, 4, or 6), and associated CDK inhibitors (CKI) such as p27 p53, and phosphorylated retino-... 

Fig. 13.10. Regulation and attack points of inhibitors of cyclin-dependent protein kinases (CKIs) in mammals. The various CKIs are activated and regulated by different signals. Inhibitory activity of the CKIs is specific for the different CDKs and CDK-cyclin combinations. p53 tumor suppressor protein p53 TGPP transforming growth factor P pRb tumor suppressor protein pRb p21 p2icipi. p27- pl6 pl6 ° CDK cyclin-dependent protein kinase Cyc cyclin E2F trans-...

Fig. 13.10 Activation and targets of inhibitors of cyclin-dependent protein kinases (CKIs) in mammals. The Ink inhibitors are activated by TGF/> and specifically inhibit the cyclinD/ CDK4/6 complexes. The inhibitors p21, p27 and p57 are activated e. g. by p53 andTGF/ and can inhibit all types of cyclin/CDK complexes. Only the major ways of CKI regulation are indicated. p53 tumor suppressor protein p53 TGF/ transforming growth factor / .

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