DYSFUNCTION OF THE MYC-INDUCED APOPTOSIS MECHANISM ACCOMPANIES C-MYC ACTIVATION IN THE TUMORIGENIC L929 CELL-LINE

Activation of the c-myc protooncogene, resulting in deregulated, over- expression of the c-Myc protein, can induce both cell proliferation an d programmed cell death (apoptosis) in nontransformed cells. Yet, c-my c activation is commonly tolerated in many tumors. This apparent parad ox can be resolved if activation of c-myc in transformed cells is asso ciated with loss of Myc-induced apoptosis. To examine this hypothesis, we characterized both the mechanisms of c-myc activation and programm ed cell death in the tumorigenic L929 cell line. We showed that activa tion of c-myc in the L929 cell line involves several distinct mechanis ms, including dysfunction of the Myc autosuppression pathway and alter ation of c-Myc protein expression. In addition, we demonstrated that L 929 cells do not undergo Myc-induced apoptosis. Analysis of somatic ce ll hybrids revealed that this abrogation of programmed cell death can be partially restored and is likely due to one or more genetic lesions . Our results support the hypothesis that the dysfunction of the Myc-i nduced apoptosis mechanism can accompany c-myc activation and provide an in vivo example illustrating two cooperative events which can contr ibute to tumor progression.