This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tracy, K.
Right arrow Articles by Macleod, K. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tracy, K.
Right arrow Articles by Macleod, K. F.

 Previous Article  |  Next Article 

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.



This article has been cited by other articles:

  • White, E., DiPaola, R. S. (2009). The Double-Edged Sword of Autophagy Modulation in Cancer. Clin. Cancer Res. 15: 5308-5316 [Abstract] [Full Text]  
  • Band, M., Joel, A., Hernandez, A., Avivi, A. (2009). Hypoxia-induced BNIP3 expression and mitophagy: in vivo comparison of the rat and the hypoxia-tolerant mole rat, Spalax ehrenbergi. FASEB J. 23: 2327-2335 [Abstract] [Full Text]  
  • Wilkinson, S., O'Prey, J., Fricker, M., Ryan, K. M. (2009). Hypoxia-selective macroautophagy and cell survival signaled by autocrine PDGFR activity. Genes Dev. 23: 1283-1288 [Abstract] [Full Text]  
  • Copetti, T., Bertoli, C., Dalla, E., Demarchi, F., Schneider, C. (2009). p65/RelA Modulates BECN1 Transcription and Autophagy. Mol. Cell. Biol. 29: 2594-2608 [Abstract] [Full Text]  
  • Metukuri, M. R., Beer-Stolz, D., Namas, R. A., Dhupar, R., Torres, A., Loughran, P. A., Jefferson, B. S., Tsung, A., Billiar, T. R., Vodovotz, Y., Zamora, R. (2009). Expression and subcellular localization of BNIP3 in hypoxic hepatocytes and liver stress. Am. J. Physiol. Gastrointest. Liver Physiol. 296: G499-G509 [Abstract] [Full Text]  
  • Pattingre, S., Bauvy, C., Carpentier, S., Levade, T., Levine, B., Codogno, P. (2009). Role of JNK1-dependent Bcl-2 Phosphorylation in Ceramide-induced Macroautophagy. J. Biol. Chem. 284: 2719-2728 [Abstract] [Full Text]  
  • Gustafsson, A. B., Gottlieb, R. A. (2009). Autophagy in Ischemic Heart Disease. Circ. Res. 104: 150-158 [Abstract] [Full Text]  
  • Chen, J.-L., Lin, H. H., Kim, K.-J., Lin, A., Forman, H. J., Ann, D. K. (2008). Novel Roles for Protein Kinase C{delta}-dependent Signaling Pathways in Acute Hypoxic Stress-induced Autophagy. J. Biol. Chem. 283: 34432-34444 [Abstract] [Full Text]  
  • Khatri, R., Schipani, E. (2008). About the importance of being desulfated. Genes Dev. 22: 2750-2754 [Abstract] [Full Text]  
  • Filiano, A. J., Bailey, C. D. C., Tucholski, J., Gundemir, S., Johnson, G. V. W. (2008). Transglutaminase 2 protects against ischemic insult, interacts with HIF1{beta}, and attenuates HIF1 signaling. FASEB J. 22: 2662-2675 [Abstract] [Full Text]  
  • Lei, L., Mason, S., Liu, D., Huang, Y., Marks, C., Hickey, R., Jovin, I. S., Pypaert, M., Johnson, R. S., Giordano, F. J. (2008). Hypoxia-Inducible Factor-Dependent Degeneration, Failure, and Malignant Transformation of the Heart in the Absence of the von Hippel-Lindau Protein. Mol. Cell. Biol. 28: 3790-3803 [Abstract] [Full Text]  
  • Zhang, H., Bosch-Marce, M., Shimoda, L. A., Tan, Y. S., Baek, J. H., Wesley, J. B., Gonzalez, F. J., Semenza, G. L. (2008). Mitochondrial Autophagy Is an HIF-1-dependent Adaptive Metabolic Response to Hypoxia. J. Biol. Chem. 283: 10892-10903 [Abstract] [Full Text]  
  • Schweers, R. L., Zhang, J., Randall, M. S., Loyd, M. R., Li, W., Dorsey, F. C., Kundu, M., Opferman, J. T., Cleveland, J. L., Miller, J. L., Ney, P. A. (2007). NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc. Natl. Acad. Sci. USA 104: 19500-19505 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»