BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy.
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.
Tracy
Kristin
K
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, USA.
Dibling
Benjamin C
BC
Spike
Benjamin T
BT
Knabb
James R
JR
Schumacker
Paul
P
Macleod
Kay F
KF
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D001483:Base Sequence; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured / Q000378:metabolism / Q000648:ultrastructure; D003676:Deferoxamine / Q000378:metabolism; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D017262:Siderophores / Q000378:metabolism
C090121:BNIP3 protein, human; C508686:BNip3 protein, mouse; D050684:E2F Transcription Factors; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D017262:Siderophores; D003676:Deferoxamine