UNCOUPLING OF P21(WAF1 CIP1/SDI1) MESSENGER-RNA AND PROTEIN EXPRESSION UPON GENOTOXIC STRESS/

The p21(WAF1/CIP1SDI1) gene is an important regulator of crucial cellu lar processes, including cell cycle control, cellular differentiation, and the response to genotoxic stress, Induction of p21 gene expressio n upon DNA damage :is,widely believed to be p53-dependent. In the pres ent study we analysed the expression of p21 following genotoxic stress , using different DNA-damaging agents and cellular systems. We found t hat the p21 response markedly varied between different cell lines and also for different genotoxic agents within the same cell line. Genotox ic induction of p21 mRNA expression can occur in the presence of p53-a ntagonists, such as overexpressed mdm-2 or human papillomavirus (HPV) E6, and in cells harbouring mutated p53 genes. Moreover, upon genotoxi c stress, p21 mRNA and protein expression were found to be uncoupled i n several cell lines. Thus, transcriptional and postranscriptional cha nges:in p21 expression following DNA damage are not necessarily linked to the intracellular p53 status but strongly depend on the individual cellular background and the type of DNA-damaging agent. Our findings indicate that p21 expression following genotoxic stress underlies a co mplex control and can be substantially modulated on the posttranscript ional level in a cell-specific manner.