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ΔNp73 enhances HIF-1α protein stability through repression of the ECV complex

Cellular responses to low oxygen conditions are mainly regulated by the Hypoxia-inducible factors (HIFs). Induction of HIF-1α in tumor cells activates the angiogenic switch and allows for metabolic adaptations. HIF-1α protein levels are tightly regulated through ubiquitin-mediated proteosomal degrad...

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Autores principales: Stantic, Marina, Wolfsberger, Johanna, Sakil, Habib A. M., Wilhelm, Margareta T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033838/
https://www.ncbi.nlm.nih.gov/pubmed/29628507
http://dx.doi.org/10.1038/s41388-018-0195-2
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author Stantic, Marina
Wolfsberger, Johanna
Sakil, Habib A. M.
Wilhelm, Margareta T.
author_facet Stantic, Marina
Wolfsberger, Johanna
Sakil, Habib A. M.
Wilhelm, Margareta T.
author_sort Stantic, Marina
collection PubMed
description Cellular responses to low oxygen conditions are mainly regulated by the Hypoxia-inducible factors (HIFs). Induction of HIF-1α in tumor cells activates the angiogenic switch and allows for metabolic adaptations. HIF-1α protein levels are tightly regulated through ubiquitin-mediated proteosomal degradation; however, high levels of HIF-1α is a common feature in many solid tumors and is thought to enhance cancer cell proliferation, migration, and survival. Here, we report that the oncogenic p73 isoform, ∆Np73, increases HIF-1α protein stability. We found that ∆Np73 represses expression of genes encoding subunits of the ECV complex, in particular Elongin C, Elongin B, Cullin 2, and Rbx1. The ECV complex is an E3 ligase complex responsible for polyubiquitinating HIF-1α. Loss of ∆Np73 increases ubiquitination of HIF-1α, leading to its degradation via the proteosomal pathway, and subsequent decrease of HIF-1α target genes. Taken together, our data demonstrates that high levels of ∆Np73 stabilize HIF-1α protein, allowing for it to accumulate and further potentiating its transcriptional activity and supporting tumor progression.
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spelling pubmed-60338382018-07-09 ΔNp73 enhances HIF-1α protein stability through repression of the ECV complex Stantic, Marina Wolfsberger, Johanna Sakil, Habib A. M. Wilhelm, Margareta T. Oncogene Article Cellular responses to low oxygen conditions are mainly regulated by the Hypoxia-inducible factors (HIFs). Induction of HIF-1α in tumor cells activates the angiogenic switch and allows for metabolic adaptations. HIF-1α protein levels are tightly regulated through ubiquitin-mediated proteosomal degradation; however, high levels of HIF-1α is a common feature in many solid tumors and is thought to enhance cancer cell proliferation, migration, and survival. Here, we report that the oncogenic p73 isoform, ∆Np73, increases HIF-1α protein stability. We found that ∆Np73 represses expression of genes encoding subunits of the ECV complex, in particular Elongin C, Elongin B, Cullin 2, and Rbx1. The ECV complex is an E3 ligase complex responsible for polyubiquitinating HIF-1α. Loss of ∆Np73 increases ubiquitination of HIF-1α, leading to its degradation via the proteosomal pathway, and subsequent decrease of HIF-1α target genes. Taken together, our data demonstrates that high levels of ∆Np73 stabilize HIF-1α protein, allowing for it to accumulate and further potentiating its transcriptional activity and supporting tumor progression. Nature Publishing Group UK 2018-04-09 2018 /pmc/articles/PMC6033838/ /pubmed/29628507 http://dx.doi.org/10.1038/s41388-018-0195-2 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Stantic, Marina
Wolfsberger, Johanna
Sakil, Habib A. M.
Wilhelm, Margareta T.
ΔNp73 enhances HIF-1α protein stability through repression of the ECV complex
title ΔNp73 enhances HIF-1α protein stability through repression of the ECV complex
title_full ΔNp73 enhances HIF-1α protein stability through repression of the ECV complex
title_fullStr ΔNp73 enhances HIF-1α protein stability through repression of the ECV complex
title_full_unstemmed ΔNp73 enhances HIF-1α protein stability through repression of the ECV complex
title_short ΔNp73 enhances HIF-1α protein stability through repression of the ECV complex
title_sort δnp73 enhances hif-1α protein stability through repression of the ecv complex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033838/
https://www.ncbi.nlm.nih.gov/pubmed/29628507
http://dx.doi.org/10.1038/s41388-018-0195-2
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