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 inhibitory effect on cyclin-dependent kinase (cdk) activity (CIP1) [2], its p53-mediated induction (WAF1) [3], and its elevated expression during differentiation (MDA6) [4]. p21(CIP1/WAF1) was also isolated in the original hamster library from which the growth arrest and DNA damage-inducible genes GADD45 and GADD153 were cloned; at least 5 independent isolates were subsequently found to encode the hamster gene, including DDIA13 and DDIA20 [5]. Given its growth inhibitory properties and its regulation 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 upregulated in response to a variety of stress signals in the absence of p53, indicating the existence of alternative mechanisms involved in regulating p21(CIP/WAF1) expression and suggesting a more generalized role for this protein during the cellular response to stress. In this review, we summarize our current knowledge concerning the mechanisms serving to regulate p21(CIP1/WAF1) gene expression in response to genotoxic and related growth-suppressive agents. We focus on the signal transduction pathways involved in the transcriptional activation of p21(CIP1/WAF1) the posttranscriptional control of p21(CIP1/WAF1) expression, and the requirement for p53 in these processes. Finally, we address the functional role of p21(CIP1/WAF1) in the cellular response to genotoxic stress. While we appreciate the fact that many of the agents discussed can lead to terminal differentiation in certain cell types, p21(CIP1/WAF1) expression during development and differentiation will not be emphasized here.