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

Ivano Amelio, Satoshi Inoue, Elke K. Markert, Arnold J. Levine, Richard A. Knight, Tak W. Mak, Gerry Melino

Research output: Contribution to journalArticle

53 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)226-231
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number1
DOIs
Publication statusPublished - Jan 6 2015

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Hypoxia-Inducible Factor 1
Neoplasms
Oxygen
Lung Neoplasms
Transcription Factors
Incidence
Proteins

Keywords

  • P53 family
  • P73
  • Tumor progression
  • Tumor vascularization
  • VEGF

ASJC Scopus subject areas

  • General

Cite this

TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation. / Amelio, Ivano; Inoue, Satoshi; Markert, Elke K.; Levine, Arnold J.; Knight, Richard A.; Mak, Tak W.; Melino, Gerry.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 1, 06.01.2015, p. 226-231.

Research output: Contribution to journalArticle

Amelio, Ivano ; Inoue, Satoshi ; Markert, Elke K. ; Levine, Arnold J. ; Knight, Richard A. ; Mak, Tak W. ; Melino, Gerry. / TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 1. pp. 226-231.
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