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Tedesco, L.; Elguero, B.; Pacin, D.G.; Senin, S.; Pollak, C.; Garcia Marchiñena, P.A.; Jurado, A.M.; Isola, M.; Labanca, M.J.; Palazzo, M.; Yankilevich, P.; Fuertes, M.; Arzt, E. "von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME" (2019) Cell Death and Disease. 10(4)
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Abstract:

Renal cell carcinoma (RCC) is the major cause of death among patients with von Hippel-Lindau (VHL) disease. Resistance to therapies targeting tumor angiogenesis opens the question about the underlying mechanisms. Previously we have described that RWDD3 or RSUME (RWD domain-containing protein SUMO Enhancer) sumoylates and binds VHL protein and negatively regulates HIF degradation, leading to xenograft RCC tumor growth in mice. In this study, we performed a bioinformatics analysis in a ccRCC dataset showing an association of RSUME levels with VHL mutations and tumor progression, and we demonstrate the molecular mechanism by which RSUME regulates the pathologic angiogenic phenotype of VHL missense mutations. We report that VHL mutants fail to downregulate RSUME protein levels accounting for the increased RSUME expression found in RCC tumors. Furthermore, we prove that targeting RSUME in RCC cell line clones carrying missense VHL mutants results in decreased early tumor angiogenesis. The mechanism we describe is that RSUME sumoylates VHL mutants and beyond its sumoylation capacity, interacts with Type 2 VHL mutants, reduces HIF-2α-VHL mutants binding, and negatively regulates the assembly of the Type 2 VHL, Elongins and Cullins (ECV) complex. Altogether these results show RSUME involvement in VHL mutants deregulation that leads to the angiogenic phenotype of RCC tumors. © 2019, The Author(s).

Registro:

Documento: Artículo
Título:von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME
Autor:Tedesco, L.; Elguero, B.; Pacin, D.G.; Senin, S.; Pollak, C.; Garcia Marchiñena, P.A.; Jurado, A.M.; Isola, M.; Labanca, M.J.; Palazzo, M.; Yankilevich, P.; Fuertes, M.; Arzt, E.
Filiación:Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)—CONICET—Partner Institute of the Max Planck Society, Godoy Cruz 2390, Buenos Aires, C1425FQD, Argentina
Departamento de Urología, Hospital Italiano de Buenos Aires, VHL Clinical Care Center, Buenos Aires, Argentina
Departamento de Patología, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Intendente Guiraldes 2160, Ciudad Universitaria, Pabellon II, 2do Piso, Buenos Aires, C1428EGA, Argentina
Año:2019
Volumen:10
Número:4
DOI: http://dx.doi.org/10.1038/s41419-019-1507-3
Título revista:Cell Death and Disease
Título revista abreviado:Cell Death Dis.
ISSN:20414889
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_20414889_v10_n4_p_Tedesco

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Citas:

---------- APA ----------
Tedesco, L., Elguero, B., Pacin, D.G., Senin, S., Pollak, C., Garcia Marchiñena, P.A., Jurado, A.M.,..., Arzt, E. (2019) . von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME. Cell Death and Disease, 10(4).
http://dx.doi.org/10.1038/s41419-019-1507-3
---------- CHICAGO ----------
Tedesco, L., Elguero, B., Pacin, D.G., Senin, S., Pollak, C., Garcia Marchiñena, P.A., et al. "von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME" . Cell Death and Disease 10, no. 4 (2019).
http://dx.doi.org/10.1038/s41419-019-1507-3
---------- MLA ----------
Tedesco, L., Elguero, B., Pacin, D.G., Senin, S., Pollak, C., Garcia Marchiñena, P.A., et al. "von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME" . Cell Death and Disease, vol. 10, no. 4, 2019.
http://dx.doi.org/10.1038/s41419-019-1507-3
---------- VANCOUVER ----------
Tedesco, L., Elguero, B., Pacin, D.G., Senin, S., Pollak, C., Garcia Marchiñena, P.A., et al. von Hippel-Lindau mutants in renal cell carcinoma are regulated by increased expression of RSUME. Cell Death Dis. 2019;10(4).
http://dx.doi.org/10.1038/s41419-019-1507-3