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This work was supported by MINECO (SAF 2010-14851), MINECO (SAF 2013-48130), Recava Network (RD12/0042/0065), Programa Prometeo Government of Ecuador and Metoxia Project-Health (F2 2009-222741) to MOL; Consepoc (S2014/BMD-2542 consepoc-CM) and MICINN (SAF 2011-29716) to JA. We thank M. Ohh (Laboratory Medicine & Pathobiology University of Toronto) for providing the RCC10 cell line.

Analysis of institutional authors

Ortiz De Landazuri Busca, ManuelAuthorAcosta-Iborra, BAuthorBalsa, EAuthorElorza, AAuthorAragones, JAuthor

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Article

Mutant versions of von Hippel-Lindau (VHL) can protect HIF1 alpha from SART1-mediated degradation in clear-cell renal cell carcinoma

Publicated to:ONCOGENE. 35 (5): 587-594 - 2016-02-04 35(5), DOI: 10.1038/onc.2015.113

Authors: Ordonez-Navadijo, A.; Fuertes-Yebra, E.; Acosta-Iborra, B.; Balsa, E.; Elorza, A.; Aragones, J.; Landazuri, M. O.;

Affiliations

Univ Autonoma Madrid, Hosp Univ Princesa, Hosp Univ Santa Cristina, Inst Invest Sanitaria,Unidad Invest, C Maestro Amadeo Vives 2-3,Edificio B,5a Plant, Madrid 28009, Spain - Author
Univ Cent Ecuador, Quito, Ecuador - Author

Abstract

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor drives the development of clear-cell renal cell carcinoma (ccRCC) through hypoxia-inducible factors (HIFs). Although ccRCC cells exhibit constitutive normoxic HIF signaling, the potential role of hypoxia in this setting is not fully understood. We show here that the ccRCC cell lines RCC4 and RCC10, which express mutant versions of VHL, have reduced HIF1? expression in hypoxia, whereas HIF2? expression is increased or not affected. Similar findings were observed in normoxia after abrogation of prolyl hydroxylase activity by siRNA or pharmacological inhibition, and by siRNA inhibition of mutant VHL. This reduction of HIF1? protein is due to proteasome-dependent degradation and is mediated by the E3 ubiquitin ligase SART1. HIF1? degradation favors ccRCC proliferation, in line with the previously recognized tumor suppressor capability of HIF1?. Our data indicate that mutant VHL can protect HIF1? from SART1-dependent degradation in normoxic conditions, but this protection is lost in hypoxic settings, favoring hypoxia-dependent ccRCC proliferation. This mechanism of HIF1? degradation might operate in some VHL-related clear-cell renal carcinomas in which the deletion of HIF1? locus does not occur.

Keywords

CancerDiseaseExpressionFactor-1-alphaGeneHif-1-alphaHif-alphaHypoxia-inducible factorsProline hydroxylationProlyl hydroxylation

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal ONCOGENE due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2016, it was in position 12/167, thus managing to position itself as a Q1 (Primer Cuartil), in the category Genetics & Heredity.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2025-06-13:

  • WoS: 7
  • Scopus: 6
  • Europe PMC: 3
  • OpenCitations: 7

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-13:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 34.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 33 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 0.25.
  • The number of mentions on the social network X (formerly Twitter): 1 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Ecuador.