期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 1, 页码 226-231出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1410609111
关键词
p73; p53 family; tumor progression; VEGF; tumor vascularization
资金
- Medical Research Council, United Kingdom
- Ministero dell'Universita e Ricerca
- MinSan/Istituto Dermatopatico dell'Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico [RF73, RF57]
- Italian Association for Cancer Research investigator grants
- Medical Research Council [MC_U132670600] Funding Source: researchfish
- MRC [MC_U132670600] Funding Source: UKRI
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 (alpha) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1 alpha 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.
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