The functions of the cdk-cyclin kinase inhibitor p21(WAF1)

p21(WAF1) plays a critical role in regulating cell growth and the cell resp onse to DNA damage. The primary targets of p21(WAF1) (hereafter referred to as p21) are the cdk-cyclins which regulate the progression of eukaryotic c ells through the cell cycle, and proliferating cell nuclear antigen (PCNA), an accessory protein of DNA polymerase delta. p21 forms complexes with a c lass of cdk-cyclins to inhibit their kinase activity and with PCNA to inhib it DNA synthesis. These distinct properties map to the N-terminal and the C -terminal regions of p21, respectively. Cell cycle arrest in G-1 (G-1 check point) following DNA damage is mediated by p53 and is deficient in p21 null cells, p53 thus upregulates p21 expression in response to DNA damage, whic h in turn inhibits cdk2-associated kinase activity. Retinoblastoma protein is regulated by cdk-cyclin kinases, and acts as a downstream target of p21 in DNA damage-induced G-1 arrest. Furthermore, accumulating evidence indica tes that p21 may play a role in maintaining G-2 arrest after DNA damage. Tr anscriptional control of p21 by factors other than p53 is critical for grow th arrest and for cell differentiation in many instances. (C) 2000 Editions scientifiques et medicales Elsevier SAS.