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.

Amelio, I., Inoue, S., Markert, E.k., Levine, A.j., Knight, R.a., Mak, T.w., et al. (2015). TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 112(1), 226-231 [10.1073/pnas.1410609111].

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

Amelio, Ivano;
2015-01-01

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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/10
English
P53 family; P73; Tumor progression; Tumor vascularization; VEGF; 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; 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; Proteolysis; Multidisciplinary
http://www.pnas.org/content/112/1/226.full.pdf+html
Amelio, I., Inoue, S., Markert, E.k., Levine, A.j., Knight, R.a., Mak, T.w., et al. (2015). TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 112(1), 226-231 [10.1073/pnas.1410609111].
Amelio, I; Inoue, S; Markert, Ek; Levine, Aj; Knight, Ra; Mak, Tw; Melino, G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/204063
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