P21(WAF1) mutations and human malignancies

During the past few years, several categories of cyclin-dependent kinase inhibitors (CDKIs), which negatively regulate cyclin/cyclin-dependent kinase (CDK) activities, were cloned. The p21(WAF1), also known as CIP1 or SDI1, was the first reported CDKI: it's expression is induced by wild-type p53. The p21(WAF1) is a potent inhibitor of most cyclin/CDK complexes and also inhibits the ability of the proliferating cell nuclear antigen (PCNA) to activate DNA polymerase d. Alterations of the cell-cycle can cause cellular transformation. We analysed 471 primary samples from 15 types of human malignancies and 36 cell lines for structural alterations of the p21(WAF1) gene. No changes were found in the coding region of p21(WAF1) gene by polymerase-chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis. Many of these tumors had a normal p53 gene: Other investigators showed that p21(WAF1) knock-out mice did not have an increased incidence of cancer, while p53 knock-out mice did. Taken together, the absence of alterations of p21(WAF1) in a series of malignancies suggests that p21(WAF1) may not have a role in either onset or progression of most human cancers. Furthermore, p53 probably activates additional, critical tumor suppressor pathways.