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Molecular and Cellular Biology, September 2007, p. 6229-6242, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.02246-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

BNIP3 Is an RB/E2F Target Gene Required for Hypoxia-Induced Autophagy{triangledown} ,{dagger}

Kristin Tracy,1,2 Benjamin C. Dibling,1 Benjamin T. Spike,1,2 James R. Knabb,1,2 Paul Schumacker,3 and Kay F. Macleod1,2*

Ben May Department for Cancer Research, Gordon Center for Integrative Sciences, W-338, The University of Chicago, 929 E 57th St., Chicago, Illinois 60637,1 Committee on Cancer Biology, The University of Chicago, Chicago, Illinois,2 Department of Medicine, Northwestern University, Chicago, Illinois3

Received 29 November 2006/ Returned for modification 29 December 2006/ Accepted 10 June 2007

Hypoxia and nutrient deprivation are environmental stresses governing the survival and adaptation of tumor cells in vivo. We have identified a novel role for the Rb tumor suppressor in protecting against nonapoptotic cell death in the developing mouse fetal liver, in primary mouse embryonic fibroblasts, and in tumor cell lines. Loss of pRb resulted in derepression of BNip3, a hypoxia-inducible member of the Bcl-2 superfamily of cell death regulators. We identified BNIP3 as a direct target of pRB/E2F-mediated transcriptional repression and showed that pRB attenuates the induction of BNIP3 by hypoxia-inducible factor to prevent autophagic cell death. BNIP3 was essential for hypoxia-induced autophagy, and its ability to promote autophagosome formation was enhanced under conditions of nutrient deprivation. Knockdown of BNIP3 reduced cell death, and remaining deaths were necrotic in nature. These studies identify BNIP3 as a key regulator of hypoxia-induced autophagy and suggest a novel role for the RB tumor suppressor in preventing nonapoptotic cell death by limiting the extent of BNIP3 induction in cells.

* Corresponding author. Mailing address: The Ben May Department for Cancer Research, The Gordon Center for Integrative Sciences, W-338, The University of Chicago, 929 E 57th St., Chicago, IL 60637. Phone: (773) 834-8309. Fax: (773) 702-4476. E-mail: kmacleod{at}huggins.bsd.uchicago.edu

{triangledown} Published ahead of print on 18 June 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, September 2007, p. 6229-6242, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.02246-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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