title: TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation.
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.
authors.affiliation: Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom;
authors.forename: Ivano
authors.initials: I
authors.lastname: Amelio
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1;
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.affiliation: The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ 08540; and.
authors.forename: Elke K
authors.initials: EK
authors.lastname: Markert
authors.affiliation: The Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ 08540; and.
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.affiliation: Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom;
authors.forename: Richard A
authors.initials: RA
authors.lastname: Knight
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1; gm89@le.ac.uk tmak@uhnresearch.ca.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom; Department of Experimental Medicine and Surgery, Biochemistry Istituto Dermopatico dell'Immacolata Laboratory, University of Rome Tor Vergata, 00133 Rome, Italy gm89@le.ac.uk tmak@uhnresearch.ca.
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D017353:Gene Deletion; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D042461:Vascular Endothelial Growth Factor A; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex
keywords: VEGF; p53 family; p73; tumor progression; tumor vascularization