Genetic dissection of c-myc apoptotic pathways

All biological functions mediated by the c-myc oncoprotein require an intac t transactivation domain (TAD). We compared TAD mutants for their ability t o promote apoptosis of 32D myeloid cells in response to interleukin-3 (IL-3 ) deprivation and exposure to chemotherapeutic drugs, and to activate ornit hine decarboxylase, an endogenous c-myc target. Different sub-regions of th e TAD were required to mediate each function. cDNA microarrays were then us ed to identify multiple c-myc-regulated transcripts, some of which were als o modulated by IL-3 or cytotoxic drugs, as well as by specific sub-regions of the TAD. Several of the c-myc-regulated transcripts had also been previo usly identified as targets for IFN-gamma. The functional consequences of th eir deregulation were manifested by a marked sensitivity of c-myc-overexpre ssing cells to IFN-gamma-mediated apoptosis, Our results establish that sev eral well-characterized functions of c-myc are separable and correlate with the expression of a novel group of target genes, some of which also mediat e the apoptotic action of IFN-gamma.