REGULATION OF P21(CIP1 WAF1) EXPRESSION BY CELLULAR STRESS - P53-DEPENDENT AND P53-INDEPENDENT MECHANISMS/

p21(CIP1/WAF1) (also referred to as SDI1, CIP1, WAF1, CAP20, and MDA6) was independently identified in several different laboratories based on its enhanced expression in senescent cells (SDI1) [1], its inhibito ry effect on cyclin-dependent kinase (cdk) activity (CIP1) [2], its p5 3-mediated induction (WAF1) [3], and its elevated expression during di fferentiation (MDA6) [4]. p21(CIP1/WAF1) was also isolated in the orig inal hamster library from which the growth arrest and DNA damage-induc ible genes GADD45 and GADD153 were cloned; at least 5 independent isol ates were subsequently found to encode the hamster gene, including DDI A13 and DDIA20 [5]. Given its growth inhibitory properties and its reg ulation by p53, it has received broad attention as a critical mediator of p53 tumor suppressive functions, most notably the G1 growth arrest and/or apoptosis that occur with certain genotoxic stresses. However, a number of recent studies have demonstrated that p21(CIP/WAF1) is up regulated in response to a variety of stress signals in the absence of p53, indicating the existence of alternative mechanisms involved in r egulating p21(CIP/WAF1) expression and suggesting a more generalized r ole for this protein during the cellular response to stress. In this r eview, we summarize our current knowledge concerning the mechanisms se rving to regulate p21(CIP1/WAF1) gene expression in response to genoto xic and related growth-suppressive agents. We focus on the signal tran sduction pathways involved in the transcriptional activation of p21(CI P1/WAF1) the posttranscriptional control of p21(CIP1/WAF1) expression, and the requirement for p53 in these processes. Finally, we address t he functional role of p21(CIP1/WAF1) in the cellular response to genot oxic stress. While we appreciate the fact that many of the agents disc ussed can lead to terminal differentiation in certain cell types, p21( CIP1/WAF1) expression during development and differentiation will not be emphasized here.