Regulation of Myc-dependent Apoptosis by p53, c-Jun N-Terminal Kinases/Stress-activated Protein Kinases, and Mdm-2

AbStraCt Deregulated overexpresslon of c-Myc (Myc) confers susceptibility to apoptosis in several cell types, but the molecular regulation of these processes has not been well established. Here we have characterized several molecular changes that may modulate Myc-dependent apoptosis. Ectopic overexpresslon of Myc in both Rati fibroblasts and human osteosarcoma cells causes a dramatic increase of cellular p53 mRNA and protein, and this induction of p53 correlates with apoptosis triggered by withdrawal of serum. Stable transfection of a wild-type human p53 gene Into Myc-transformed cells further potentiates apoptosis. Anticancer agents vinblastine and nocodazole also Induce apoptosis in Myc-transformed Rati fibroblasts but are cytostatic to the same cells without Myc overexpresslon. 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 Idnase (JNK/SAPK) activity, whereas this JNKFSAPK activation is absent in stress-treated cells without Myc overexpression. Moreover, overexpression of the Mdm-2 gene in Rati-myc cells significantly inhibits apoptosis induced by low serum but has little effect on apoptosis triggered by chemotherapeutic drugs. Interestingly, differential inhibition by Mdm-2 paralleled differential activation of p46 JNK/SAPK. Thus, our data support a functional involvement of p53 in Myc-dependent apoptosis and implicate potential regulatory roles for JNK/SAPK and Mdm-2 pathways in the regulation of apoptosis in Myc-transformed tumor cells