Abstract
p53-dependent apoptosis is a major determinant of its tumor suppressor activity and can be triggered by hypoxia. No p53 target is known to be induced by p53 or to mediate p53-dependent apoptosis during hypoxia. We report that p53 can directly upregulate expression of Bnip3L, a cell death inducer. During hypoxia, Bnip3L is highly induced in wild-type p53-expressing cells, in part due to increased recruitment of p53 and CBP to Bnip3L. Apoptosis is reduced in hypoxia-exposed cells with functional p53 following Bnip3L knockdown. In vivo, Bnip3L knockdown promotes tumorigenicity of wild-type versus mutant p53-expressing tumors. Thus, Bnip3L, capable of attenuating tumorigenicity, mediates p53-dependent apoptosis under hypoxia, which provides a novel understanding of p53 in tumor suppression.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Blotting, Western
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CREB-Binding Protein
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Caspase 3
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Caspases / metabolism
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Cell Hypoxia
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Cell Line, Tumor
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Cell Proliferation
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Chromatin Immunoprecipitation
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Cisplatin / pharmacology
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Doxycycline / pharmacology
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Fluorouracil / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Genes, Reporter / genetics
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Glucose Transporter Type 1
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Humans
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Immunohistochemistry
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In Situ Hybridization
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Membrane Proteins / physiology*
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Mice
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Mice, Nude
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Monosaccharide Transport Proteins / metabolism
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Neoplasms / genetics
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Neoplasms / metabolism
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Neoplasms / pathology*
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Nuclear Proteins / metabolism
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Oligonucleotide Array Sequence Analysis
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Protein Binding / drug effects
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / physiology*
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RNA Interference
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RNA, Small Interfering / genetics
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Repressor Proteins / genetics
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Trans-Activators / metabolism
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Transfection
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Protein p53 / physiology*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Tumor Suppressor Proteins / physiology*
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Xenograft Model Antitumor Assays
Substances
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BNIP3 protein, human
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BNIP3L protein, human
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Glucose Transporter Type 1
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Membrane Proteins
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Monosaccharide Transport Proteins
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Nuclear Proteins
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Repressor Proteins
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SLC2A1 protein, human
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Trans-Activators
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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tetracycline resistance-encoding transposon repressor protein
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CREB-Binding Protein
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CREBBP protein, human
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Crebbp protein, mouse
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CASP3 protein, human
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Casp3 protein, mouse
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Caspase 3
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Caspases
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Doxycycline
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Cisplatin
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Fluorouracil