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Molecular and Cellular Biology, July 2001, p. 4725-4736, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4725-4736.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Myc Potentiates Apoptosis by Stimulating Bax Activity at the Mitochondria†

Erinn L. Soucie,1,2 Matthew G. Annis,3 John Sedivy,4 Jorge Filmus,2,5 Brian Leber,3,6 David W. Andrews,3 and Linda Z. Penn1,2,*

Division of Cell and Molecular Biology, Ontario Cancer Institute,1 Department of Medical Biophysics, University of Toronto,2 and Division of Cancer Biology Research, Sunnybrook and Women's College Health Science Centre,5 Toronto, and Departments of Biochemistry3 and Medicine and Laboratory Medicine,6 McMaster University, Hamilton, Ontario, Canada, and Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island4

Received 23 October 2000/Returned for modification 5 December 2000/Accepted 19 April 2001

The ability of the c-Myc oncoprotein to potentiate apoptosis has been well documented; however, the mechanism of action remains ill defined. We have previously identified spatially distinct apoptotic pathways within the same cell that are differentially inhibited by Bcl-2 targeted to either the mitochondria (Bcl-acta) or the endoplasmic reticulum (Bcl-cb5). We show here that in Rat1 cells expressing an exogenous c-myc allele, distinct apoptotic pathways can be inhibited by Bcl-2 or Bcl-acta yet be distinguished by their sensitivity to Bcl-cb5 as either susceptible (serum withdrawal, taxol, and ceramide) or refractory (etoposide and doxorubicin). Myc expression and apoptosis were universally associated with Bcl-acta and not Bcl-cb5, suggesting that Myc acts downstream at a point common to these distinct apoptotic signaling cascades. Analysis of Rat1 c-myc null cells shows these same death stimuli induce apoptosis with characteristic features of nuclear condensation, membrane blebbing, poly (ADP-ribose) polymerase cleavage, and DNA fragmentation; however, this Myc-independent apoptosis is not inhibited by Bcl-2. During apoptosis, Bax translocation to the mitochondria occurs in the presence or absence of Myc expression. Moreover, Bax mRNA and protein expression remain unchanged in the presence or absence of Myc. However, in the absence of Myc, Bax is not activated and cytochrome c is not released into the cytoplasm. Reintroduction of Myc into the c-myc null cells restores Bax activation, cytochrome c release, and inhibition of apoptosis by Bcl-2. These results demonstrate a role for Myc in the regulation of Bax activation during apoptosis. Moreover, apoptosis that can be triggered in the absence of Myc provides evidence that signaling pathways exist which circumvent Bax activation and cytochrome c release to trigger caspase activation. Thus, Myc increases the cellular competence to die by enhancing disparate apoptotic signals at a common mitochondrial amplification step involving Bax activation and cytochrome c release.

* Corresponding author. Mailing address: Ontario Cancer Institute, 610 University Ave., Rm. 9-628, Toronto, Ontario, Canada M5G 2M9. Phone: (416) 946-2276. Fax: (416) 946-2840. E-mail: lpenn{at}uhnres.utoronto.ca.

dagger This paper is dedicated to the memory of Arnold Greenberg.

Molecular and Cellular Biology, July 2001, p. 4725-4736, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4725-4736.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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