BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy

Kristin Tracy, Benjamin C. Dibling, Benjamin T. Spike, James R. Knabb, Paul Schumacker, Kay F. Macleod*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

257 Scopus citations


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 Kb 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.

Original languageEnglish (US)
Pages (from-to)6229-6242
Number of pages14
JournalMolecular and cellular biology
Issue number17
StatePublished - Sep 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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