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Vol. 17, No. 2, pp. 240-255, January 15, 2003

RESEARCH PAPER
c-MYC apoptotic function is mediated by NRF-1 target genes

Fionnuala Morrish, Christopher Giedt, and David Hockenbery1

Fred Hutchinson Cancer Research Center, Division of Molecular Medicine, Seattle, Washington 98109, USA

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.

[Key Words: Apoptosis; c-MYC; NRF-1; mitochondrial biogenesis; Supplemental material is available at http://www.genesdev.org.]

1 Corresponding author.

GENES & DEVELOPMENT 17:240-255 © 2003 by Cold Spring Harbor Laboratory Press  ISSN 0890-9369/03 $5.00
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