Genetic dissection of c-myc apoptotic pathways

Oncogene. 2000 Jun 29;19(28):3200-12. doi: 10.1038/sj.onc.1203636.

Abstract

All biological functions mediated by the c-myc oncoprotein require an intact transactivation domain (TAD). We compared TAD mutants for their ability to promote apoptosis of 32D myeloid cells in response to interleukin-3 (IL-3) deprivation and exposure to chemotherapeutic drugs, and to activate ornithine decarboxylase, an endogenous c-myc target. Different sub-regions of the TAD were required to mediate each function. cDNA microarrays were then used to identify multiple c-myc-regulated transcripts, some of which were also 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 previously identified as targets for IFN-gamma. The functional consequences of their deregulation were manifested by a marked sensitivity of c-myc-overexpressing cells to IFN-gamma-mediated apoptosis. Our results establish that several well-characterized functions of c-myc are separable and correlate with the expression of a novel group of target genes, some of which also mediate the apoptotic action of IFN-gamma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Gene Expression
  • Interferon-gamma / pharmacology
  • Mice
  • Ornithine Decarboxylase / genetics
  • Ornithine Decarboxylase / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA
  • Recombinant Proteins
  • Tumor Cells, Cultured

Substances

  • Proto-Oncogene Proteins c-myc
  • Recombinant Proteins
  • RNA
  • Interferon-gamma
  • Ornithine Decarboxylase