TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation.

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.
Mesh Terms:
Adenocarcinoma, Animals, Cell Line, Tumor, DNA-Binding Proteins, Disease Progression, Gene Deletion, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, In Vitro Techniques, Lung Neoplasms, Mice, Inbred C57BL, Neoplasms, Neovascularization, Pathologic, Nuclear Proteins, Proteasome Endopeptidase Complex, Protein Binding, Proteolysis, Proto-Oncogene Proteins c-mdm2, Signal Transduction, Survival Analysis, Tumor Protein p73, Tumor Suppressor Proteins, Ubiquitin, Ubiquitination, Vascular Endothelial Growth Factor A, Xenograft Model Antitumor Assays
Proc. Natl. Acad. Sci. U.S.A.
Date: Jan. 06, 2015
Download Curated Data For This Publication
209374
Switch View:
  • Interactions 2