Cell cycle cyclin-dependent kinase inhibitors

Barres BA, Lazar MA, Raff MC 1994 A novel role for thyroid hormone, glucocorticoids and retinoic acid in timing oligodendrocyte development. Development 120 1097-1108 deNooij JC, Letendre MA, Hariharan IK 1996 A cyclin-dependent kinase inhibitor, Dacapo, is necessary for timely exit from the cell cycle during Drosophila embryogenesis. Cell 87 ... 

Durand B, Gao FB, Raff M 1997 Accumulation of the cyclin-dependent kinase inhibitor p27/ Kipl and the timing of oligodendrocyte differentiation. EMBO J 16 306-317 Durand B, Fero ML, Roberts JM, Raff MC 1998 p27Kipl alters the response of cells to mitogen and is part of a cell-intrinsic timer that arrests the cell cycle and initiates differentiation. Curr Biol 8 431-440... 

Hong Y, Roy R, Ambros V 1998 Developmental regulation of a cyclin-dependent kinase inhibitor controls postembryonic cell cycle progression in Caenorhabditis elegant. Development 125 3585—3597... 

S. Chakravarty, S. Dugar (2002). Inhibitors of p38a MAL kinase. A m<. Rep. Med. Chem. 37 111. Y. Dai, S. Grant (2003). Cyclin-dependent kinase inhibitors. Curr. Opin. Pharmacol. 3 362-370. S. D. Kimball, K. R. Webster (2001). Cell cycle kinases and checkpoint regulation in cancer. Annu. Rep. Med. Chem. 36 139. 

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. 

Sielecki, T.M., Boylan, J.F., Benfield, P.A., Trainor, G.L. Cyclin-dependent kinase inhibitors useful targets in cell cycle regulation. Journal of Medicinal Chemistry 2000, 43, 1-18. 

The cyclin-dependent kinase inhibitor p21 is another downstream effector of p53 [161-163], There is evidence for p53-independent induction of p21 [162], and under these conditions the protein may be responsible for cisplatin-induced apoptosis [210][211], The p21 protein usually plays a protective role in response to cisplatin [212] [213], however, an effect which correlated with enhanced repair of a damaged reporter plasmid [212-214], These observations are consistent with the hypothesis that DNA-damage induced p53 activates a G, cell cycle arrest through p21, affording the cell time to repair the lesions and precluding the genetic instability produced by replication of damaged DNA. In accord with this model, the addition of p21 to cell free extracts blocked DNA replication but not excision repair... 

Katchanov J, Haims C, Gertz K, Hauck L, Waeber C, Hirt L, Priller J, von Harsdorf R, Bmck W, Horlnagl H, Dirnagl U, Bhide PG, Endres M (2001) Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death. J Neurosci 21 5054—5053. 

Cannabinoids have been shown to induce cell cycle arrest in breast carcinoma (De Petrocellis et al. 1998), prostate carcinoma (Melck et al. 2000) and thyroid epithelioma cells (Bifulco et al. 2001). In breast carcinoma cells this has been ascribed to the inhibition of adenylyl cyclase and the cAMP/protein kinase A (PKA) pathway (Table 1). PKA phosphorylates and inhibits Raf-1, so cannabinoids prevent the inhibition of Raf-1 and induce prolonged activation of the Raf-l/MEK/ERK signalling cascade (Melck et al 1999). Cannabinoid-induced inhibition of thyroid epithelioma cell proliferation has been attributed to the induction of the cyclin-dependent kinase inhibitor p27 P (Portella et al. 2003). 

Liua, W.-k., Ho, J.C.K., Ng, T.B. Suppression of cell cycle progression by a fungal lectin activation of cyclin-dependent kinase inhibitors. Biochem. Pharmacol. 2001, 61, 33-37... 

The cyclin-dependent kinase inhibitors such as p21 and pl6 proteins play central roles in this process. These proteins exert their functions by combining with cyclins/CDKs complexes, conducting finally to the blockage of the cell cycle at Gl-S checkpoint [131,132]. 

Fig. 18.8. Control of the Gl/S transition in the cell cycle. The genes encoding cyclins and CDKs are oncogenes, and the gene encoding the Retinoblastoma protein (Rb) is a tumor suppressor gene. Abbreviations CDK, cyclin- dependent kinase CDKI, cyclin-dependent kinase inhibitor.

Shen JC, Klein RD, Wei Q, Guan Y, Contois JH, Wang TT, Chang S, Hursting SD. Low-dose genistein induces cyclin-dependent kinase inhibitors and G1 cell-cycle arrest in human prostate cancer cells. Mol Carcinogen 2000 29 92-102. 

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