c-MYC apoptotic function is mediated by NRF-1 target genes.
A detailed understanding of the signaling pathways by which c-Myc elicits apoptosis has proven elusive. In the current study, we have evaluated whether the activation of the mitochondrial apoptotic signaling pathway is linked to c-Myc induction of a subset of genes involved in mitochondrial biogenesis. Cytochrome c and other nuclear-encoded mitochondrial genes are regulated by the transcription factor nuclear respiratory factor-1 (NRF-1). The consensus binding sequence (T/C)GCGCA(C/T)GCGC(A/G) of NRF-1 includes a noncanonical CA(C/T)GCG Myc:MAX binding site. In this study, we establish a link between the induction of NRF-1 target genes and sensitization to apoptosis on serum depletion. We demonstrate, by using Northern analysis, transactivation assays, and in vitro and in vivo promoter binding assays that cytochrome c is a direct target of c-Myc. Like c-Myc, NRF-1 overexpression sensitizes cells to apoptosis on serum depletion. We also demonstrate that selective interference with c-Myc induction of NRF-1 target genes by using a dominant-negative NRF-1 prevented c-Myc-induced apoptosis, without affecting c-Myc-dependent proliferation. These results suggest that c-myc expression leads to mitochondrial dysfunction and apoptosis by deregulating genes involved in mitochondrial function.
Morrish
Fionnuala
F
Fred Hutchinson Cancer Research Center, Division of Molecular Medicine, Seattle, Washington 98109, USA.
Giedt
Christopher
C
Hockenbery
David
D
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002455:Cell Division; D002460:Cell Line; D003574:Cytochrome c Group / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D017353:Gene Deletion; D015870:Gene Expression; D016259:Genes, myc; D051379:Mice; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D051265:NF-E2-Related Factor 1; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D011401:Promoter Regions, Genetic; D051381:Rats; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics*; D015533:Transcriptional Activation
D003574:Cytochrome c Group; D004268:DNA-Binding Proteins; D051265:NF-E2-Related Factor 1; C495632:Nfe2l1 protein, rat; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D015534:Trans-Activators; D004247:DNA