Abstract:
Somatic mutations or loss of von Hippel-Lindau (pVHL) happen in the majority of VHL disease tumors, which present a constitutively active Hypoxia Inducible Factor (HIF), essential for tumor growth. Recently described mechanisms for pVHL modulation shed light on the open question of the HIF/pVHL pathway regulation. The aim of the present study was to determine the molecular mechanism by which RSUME stabilizes HIFs, by studying RSUME effect on pVHL function and to determine the role of RSUME on pVHL-related tumor progression. We determined that RSUME sumoylates and physically interacts with pVHL and negatively regulates the assembly of the complex between pVHL, Elongins and Cullins (ECV), inhibiting HIF-1 and 2α ubiquitination and degradation. We found that RSUME is expressed in human VHL tumors (renal clear-cell carcinoma (RCC), pheochromocytoma and hemangioblastoma) and by overexpressing or silencing RSUME in a pVHL-HIF-oxygen-dependent degradation stability reporter assay, we determined that RSUME is necessary for the loss of function of type 2 pVHL mutants. The functional RSUME/pVHL interaction in VHL-related tumor progression was further confirmed using a xenograft assay in nude mice. RCC clones, in which RSUME was knocked down and express either pVHL wt or type 2 mutation, have an impaired tumor growth, as well as HIF-2α, vascular endothelial growth factor A and tumor vascularization diminution. This work shows a novel mechanism for VHL tumor progression and presents a new mechanism and factor for targeting tumor-related pathologies with pVHL/HIF altered function. © 2015 Macmillan Publishers Limited. All rights reserved.
Registro:
Documento: |
Artículo
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Título: | RSUME inhibits VHL and regulates its tumor suppressor function |
Autor: | Gerez, J.; Tedesco, L.; Bonfiglio, J.J.; Fuertes, M.; Barontini, M.; Silberstein, S.; Wu, Y.; Renner, U.; Paéz-Pereda, M.; Holsboer, F.; Stalla, G.K.; 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 Fisiologiá y Biologiá Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina Center for Endocrinological Investigations (CEDIE), Hospital de Ninõs R. Gutiérrez, Buenos Aires, Argentina Department of Clinical Research, Max Planck Institute of Psychiatry, Munich, Germany
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Palabras clave: | cullin; elongin; hypoxia inducible factor 1; hypoxia inducible factor 2alpha; rwd domain containing protein sumo enhancer protein; SUMO protein; unclassified drug; vasculotropin A; von Hippel Lindau protein; RSUME protein, human; transcription factor; VHL protein, human; von Hippel Lindau protein; animal experiment; animal model; Article; assay; cancer inhibition; clear cell carcinoma; controlled study; gene mutation; gene overexpression; gene silencing; hemangioblastoma; human; human tissue; kidney carcinoma; male; mouse; mutant; nonhuman; pheochromocytoma; priority journal; protein degradation; protein expression; protein function; protein protein interaction; tumor growth; tumor vascularization; ubiquitination; xenograft; adrenal tumor; animal; cerebellum tumor; Chlorocebus aethiops; COS 1 cell line; disease course; down regulation; gene expression regulation; genetics; nude mouse; pathology; physiology; tumor cell culture; tumor suppressor gene; Adrenal Gland Neoplasms; Animals; Cercopithecus aethiops; Cerebellar Neoplasms; COS Cells; Disease Progression; Down-Regulation; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Hemangioblastoma; Humans; Male; Mice; Mice, Nude; Pheochromocytoma; Transcription Factors; Tumor Cells, Cultured; Von Hippel-Lindau Tumor Suppressor Protein |
Año: | 2015
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Volumen: | 34
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Número: | 37
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Página de inicio: | 4855
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Página de fin: | 4866
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DOI: |
http://dx.doi.org/10.1038/onc.2014.407 |
Título revista: | Oncogene
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Título revista abreviado: | Oncogene
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ISSN: | 09509232
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CODEN: | ONCNE
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CAS: | vasculotropin A, 489395-96-2; RSUME protein, human; Transcription Factors; VHL protein, human; Von Hippel-Lindau Tumor Suppressor Protein
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Registro: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09509232_v34_n37_p4855_Gerez |
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Citas:
---------- APA ----------
Gerez, J., Tedesco, L., Bonfiglio, J.J., Fuertes, M., Barontini, M., Silberstein, S., Wu, Y.,..., Arzt, E.
(2015)
. RSUME inhibits VHL and regulates its tumor suppressor function. Oncogene, 34(37), 4855-4866.
http://dx.doi.org/10.1038/onc.2014.407---------- CHICAGO ----------
Gerez, J., Tedesco, L., Bonfiglio, J.J., Fuertes, M., Barontini, M., Silberstein, S., et al.
"RSUME inhibits VHL and regulates its tumor suppressor function"
. Oncogene 34, no. 37
(2015) : 4855-4866.
http://dx.doi.org/10.1038/onc.2014.407---------- MLA ----------
Gerez, J., Tedesco, L., Bonfiglio, J.J., Fuertes, M., Barontini, M., Silberstein, S., et al.
"RSUME inhibits VHL and regulates its tumor suppressor function"
. Oncogene, vol. 34, no. 37, 2015, pp. 4855-4866.
http://dx.doi.org/10.1038/onc.2014.407---------- VANCOUVER ----------
Gerez, J., Tedesco, L., Bonfiglio, J.J., Fuertes, M., Barontini, M., Silberstein, S., et al. RSUME inhibits VHL and regulates its tumor suppressor function. Oncogene. 2015;34(37):4855-4866.
http://dx.doi.org/10.1038/onc.2014.407