REGULATION OF MYC-DEPENDENT APOPTOSIS BY P53, C-JUN N-TERMINAL KINASES STRESS-ACTIVATED PROTEIN-KINASES, AND MDM-2

Deregulated overexpression of c-Myc (Myc) confers susceptibility to ap optosis in several cell types, but the molecular regulation of these p rocesses has not been well established, Here we have characterized sev eral molecular changes that may modulate Myc-dependent apoptosis, Ecto pic overexpression of Myc in both Rat1 fibroblasts and human osteosarc oma cells causes a dramatic increase of cellular p53 mRNA and protein, and this induction of p53 correlates with apoptosis triggered by with drawal of serum, Stable transfection of a wild-type human p53 gene int o Myc-transformed cells further potentiates apoptosis, Anticancer agen ts vinblastine and nocodazole also induce apoptosis in Myc-transformed Rat1 fibroblasts but are cytostatic to the same cells without Myc ove rexpression. We demonstrate that induction of Myc-dependent apoptosis in these cells is specifically associated with an activation of p46 c- Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activ ity, whereas this JNK/SAPK activation is absent in stress-treated cell s without Myc overexpression. Moreover, overexpression of the Mdm-2 ge ne in Rat1-myc cells significantly inhibits apoptosis induced by low s erum but has little effect on apoptosis triggered by chemotherapeutic drugs, Interestingly, differential inhibition by Mdm-2 paralleled diff erential activation of p46 JNK/SAPK. Thus, our data support a function al involvement of p53 in Myc-dependent apoptosis and implicate potenti al regulatory roles for JNK/SAPK and Mdm-2 pathways in the regulation of apoptosis in Myc-transformed tumor cells.