c-Myc antagonizes the effect of p53 on apoptosis and p21(WAF1) transactivation in K562 leukemia cells

c-myc protooncogene positively regulates cell proliferation and overexpress ion of c-myc is found in many solid tumors and leukemias, In the present st udy we used the K562 human myeloid leukemia cell line as a model to study t he functional interaction between c-Myc and p53. Using two different method s, we generated K562 transfectant cell lines with conditional expression of either c-Myc or p53. The cells expressed the p53(Vall35) mutant, which ado pts a mild-type conformation at 32 degrees C, while c-Myc induction was ach ieved with a zinc-inducible expression vector. We found that p53 in mild-ty pe conformation induces growth arrest and apoptosis of K562. Expression of c-Myc significantly attenuated apoptosis and impaired the transcriptional a ctivity of D53 on p21(WAF1), fax and cytomegalovirus promoters. The impairm ent of p21(WAF1) transactivation by c-Myc was confirmed by transfection of a c-Myc-estrogen receptor fusion protein and by induction of c-myc by zinc in transfected cells. Also, p53-mediated up-regulation of p21(WAF1) mRNA pr otein mere significantly reduced by Myc, while Bas levels were unaffected. Consistently, c- Myc increased cyclin-dependent kinase 2 activity in K562 c ells expressing p53 in wild-type conformation These results suggest that c- Myc overexpression may antagonize the pro-apoptotic function of p53, thus p roviding a molecular mechanism for frequently observed deregulation of c-my c in human cancer.