Genetic dissection of c-myc apoptotic pathways.
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.
Section of Hematology/Oncology, The Children's Hospital of Pittsburgh, Pennsylvania 15213, USA.
C E
CE
Nesbit
J M
JM
Tersak
L E
LE
Grove
A
A
Drzal
H
H
Choi
E V
EV
Prochownik
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015870:Gene Expression; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012313:RNA; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; D012313:RNA; D007371:Interferon-gamma; D009955:Ornithine Decarboxylase