Abstract
Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activation are associated with cancer progression. Here, we demonstrate that the transcription factor TAp73 opposes HIF-1 activity through a nontranscriptional mechanism, thus affecting tumor angiogenesis. TAp73-deficient mice have an increased incidence of spontaneous and chemically induced tumors that also display enhanced vascularization. Mechanistically, TAp73 interacts with the regulatory subunit (α) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1α polyubiquitination and consequent proteasomal degradation in an oxygen-independent manner. In human lung cancer datasets, TAp73 strongly predicts good patient prognosis, and its expression is associated with low HIF-1 activation and angiogenesis. Our findings, supported by in vivo and clinical evidence, demonstrate a mechanism for oxygen-independent HIF-1 regulation, which has important implications for individualizing therapies in patients with cancer.
Keywords:
VEGF; p53 family; p73; tumor progression; tumor vascularization.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Adenocarcinoma of Lung
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Animals
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Cell Line, Tumor
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DNA-Binding Proteins / metabolism*
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Disease Progression
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Gene Deletion
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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In Vitro Techniques
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Mice, Inbred C57BL
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Neoplasms / blood supply*
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Neoplasms / metabolism*
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Neovascularization, Pathologic
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Nuclear Proteins / metabolism*
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Proteasome Endopeptidase Complex / metabolism
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Protein Binding
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Proteolysis*
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Signal Transduction
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Survival Analysis
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Tumor Protein p73
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin / metabolism
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Ubiquitination
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Vascular Endothelial Growth Factor A / metabolism
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Xenograft Model Antitumor Assays
Substances
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DNA-Binding Proteins
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Hypoxia-Inducible Factor 1, alpha Subunit
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Nuclear Proteins
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TP73 protein, human
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Trp73 protein, mouse
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Tumor Protein p73
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Tumor Suppressor Proteins
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Ubiquitin
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Vascular Endothelial Growth Factor A
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Proto-Oncogene Proteins c-mdm2
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Proteasome Endopeptidase Complex