RSUME inhibits VHL and regulates its tumor suppressor function

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 path...

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Autores principales:	Gerez, Juan Atilio, Bonfiglio, Juan José, Páez Pereda, Marcelo
Publicado:	2015
Materias:	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 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
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09509232_v34_n37_p4855_Gerez http://hdl.handle.net/20.500.12110/paper_09509232_v34_n37_p4855_Gerez
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	paper:paper_09509232_v34_n37_p4855_Gerez2023-06-08T15:54:50Z RSUME inhibits VHL and regulates its tumor suppressor function Gerez, Juan Atilio Bonfiglio, Juan José Páez Pereda, Marcelo 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 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. Fil:Gerez, J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Bonfiglio, J.J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Paéz-Pereda, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2015 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09509232_v34_n37_p4855_Gerez http://hdl.handle.net/20.500.12110/paper_09509232_v34_n37_p4855_Gerez
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	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
spellingShingle	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 Gerez, Juan Atilio Bonfiglio, Juan José Páez Pereda, Marcelo RSUME inhibits VHL and regulates its tumor suppressor function
topic_facet	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
description	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.
author	Gerez, Juan Atilio Bonfiglio, Juan José Páez Pereda, Marcelo
author_facet	Gerez, Juan Atilio Bonfiglio, Juan José Páez Pereda, Marcelo
author_sort	Gerez, Juan Atilio
title	RSUME inhibits VHL and regulates its tumor suppressor function
title_short	RSUME inhibits VHL and regulates its tumor suppressor function
title_full	RSUME inhibits VHL and regulates its tumor suppressor function
title_fullStr	RSUME inhibits VHL and regulates its tumor suppressor function
title_full_unstemmed	RSUME inhibits VHL and regulates its tumor suppressor function
title_sort	rsume inhibits vhl and regulates its tumor suppressor function
publishDate	2015
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09509232_v34_n37_p4855_Gerez http://hdl.handle.net/20.500.12110/paper_09509232_v34_n37_p4855_Gerez
work_keys_str_mv	AT gerezjuanatilio rsumeinhibitsvhlandregulatesitstumorsuppressorfunction AT bonfigliojuanjose rsumeinhibitsvhlandregulatesitstumorsuppressorfunction AT paezperedamarcelo rsumeinhibitsvhlandregulatesitstumorsuppressorfunction
_version_	1768545101627260928

RSUME inhibits VHL and regulates its tumor suppressor function

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