Apoptosis-inducing levels of uv radiation and proteasome inhibitors produce opposite effects on p21(WAF1) in human melanoma cells

The stability of p21(WAF1) and p53 is increased by UV radiation or proteaso me inhibitors in normal and some tumor cells. However, p21(WAF1) can either stimulate in vitro assembly of active cyclin-kinase complexes at low conce ntrations or inhibit this activity at high concentrations. Also, ectopic p2 1(WAF1) over-expression has been reported to promote or suppress apoptosis, depending on the target cells. We have investigated changes in p21(WAF1) e xpression as a result of exposure to either 25 J/m(2) UV or 10 mu M MG-115 proteasome inhibitor, both of which cause apoptosis in human C8161 melanoma cells. p21(WAF1) mRNA increased in response to UV irradiation but failed t o accumulate at the protein level because of its early UV-activated degrada tion counteracted by proteasome inhibition. UV-mediated loss of p21(WAF1) p rotein preceding induction of p53 and cell death was greater in non-metasta tic than in metastatic C8161 melanoma cells. No loss in p21(WAF1) occurred with apoptosis induced by 10 mu M proteasome inhibitors MG-115 or lactacyst in, mediated by over-expression of p21(WAF1). Our results suggest that cond itions causing prolonged or permanent changes in basal levels of p21(WAF1) may impair its reversible cell-cycle checkpoint function, leading to irreve rsible growth arrest or cell death. Int, J. Cancer 86:462-467, 2000. (C) 20 00 Wiley-Liss, Inc.