Artículo

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. "RSUME inhibits VHL and regulates its tumor suppressor function" (2015) Oncogene. 34(37):4855-4866
Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

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
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
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
Volumen:34
Número:37
Página de inicio:4855
Página de fin:4866
DOI: http://dx.doi.org/10.1038/onc.2014.407
Título revista:Oncogene
Título revista abreviado:Oncogene
ISSN:09509232
CODEN:ONCNE
CAS:vasculotropin A, 489395-96-2; RSUME protein, human; Transcription Factors; VHL protein, human; Von Hippel-Lindau Tumor Suppressor Protein
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09509232_v34_n37_p4855_Gerez

Referencias:

  • Carbia-Nagashima, A., Gerez, J., Perez-Castro, C., Paez-Pereda, M., Silberstein, S., Stalla, G.K., RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1alpha during hypoxia (2007) Cell, 131, pp. 309-323
  • Geiss-Friedlander, R., Melchior, F., Concepts in sumoylation: A decade on (2007) Nat Rev Mol Cell Biol, 8, pp. 947-956
  • Hay, R.T., SUMO: A history of modification (2005) Mol Cell, 18, pp. 1-12
  • Druker, J., Liberman, A.C., Antunica-Noguerol, M., Gerez, J., Paez-Pereda, M., Rein, T., RSUME enhances glucocorticoid receptor SUMOylation and transcriptional activity (2013) Mol Cell Biol, 33, pp. 2116-2127
  • Gerez, J., Fuertes, M., Tedesco, L., Silberstein, S., Sevlever, G., Paez-Pereda, M., In silico structural and functional characterization of the RSUME splice variants (2013) PLoS One, 8, p. e57795
  • Huang, C.C., Tu, S.H., Lien, H.H., Jeng, J.Y., Huang, C.S., Huang, C.J., Concurrent gene signatures for han Chinese breast cancers (2013) PLoS ONE, 8, p. e76421
  • Schneider, B.P., Li, L., Miller, K., Flockhart, D., Radovich, M., Hancock, B.A., Genetic associations with taxane-induced neuropathy by a genome-wide association study (GWAS) in E5103 (2011) J Clin Oncol, 29. , Supplementary Abstract 1000
  • Bergmann, T.K., Vach, W., Feddersen, S., Eckhoff, L., Green, H., Herrstedt, J., GWASbased association between RWDD3 and TECTA variants and paclitaxel induced neuropathy could not be confirmed in Scandinavian ovarian cancer patients (2013) Acta Oncol, 52, pp. 871-874
  • Rojewska, E., Korostynski, M., Przewlocki, R., Przewlocka, B., Mika, J., Expression profiling of genes modulated by minocycline in a rat model of neuropathic pain (2014) Mol Pain, 10, p. 47
  • Willi-Monnerat, S., Migliavacca, E., Surdez, D., Delorenzi, M., Luthi-Carter, R., Terskikh, A.V., Comprehensive spatiotemporal transcriptomic analyses of the ganglionic eminences demonstrate the uniqueness of its caudal subdivision (2008) Mol Cell Neurosci, 37, pp. 845-856
  • Semenza, G.L., Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1 (1999) Annu Rev Cell Dev Biol, 15, pp. 551-578
  • Brahimi-Horn, M.C., Pouyssegur, J., HIF at a glance (2009) J Cell Sci, 122, pp. 1055-1057
  • Kaelin, W.G., Jr., Ratcliffe, P.J., Oxygen sensing by metazoans: The central role of the HIF hydroxylase pathway (2008) Mol Cell, 30, pp. 393-402
  • Keith, B., Johnson, R.S., Simon, M.C., HIF1alpha and HIF2alpha: Sibling rivalry in hypoxic tumour growth and progression (2012) Nat Rev Cancer, 12, pp. 9-22
  • Pugh, C.W., O'Rourke, J.F., Nagao, M., Gleadle, J.M., Ratcliffe, P.J., Activation of hypoxiainducible factor-1; Definition of regulatory domains within the alpha subunit (1997) J Biol Chem, 272, pp. 11205-11214
  • Berra, E., Pouyssegur, J., The silencing approach of the hypoxia-signaling pathway (2007) Methods Enzymol, 435, pp. 107-121
  • Greer, S.N., Metcalf, J.L., Wang, Y., Ohh, M., The updated biology of hypoxiainducible factor (2012) EMBO J, 31, pp. 2448-2460
  • Kaelin, W.G., Jr., Molecular basis of the VHL hereditary cancer syndrome (2002) Nat Rev Cancer, 2, pp. 673-682
  • Yu, F., White, S.B., Zhao, Q., Lee, F.S., HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation (2001) Proc Natl Acad Sci USA, 98, pp. 9630-9635
  • Schwartz, A.L., Ciechanover, A., Targeting proteins for destruction by the ubiquitin system: Implications for human pathobiology (2009) Annu Rev Pharmacol Toxicol, 49, pp. 73-96
  • Semenza, G.L., Oxygen sensing, homeostasis, and disease (2011) N Engl J Med, 365, pp. 537-547
  • Nunez-O'Mara, A., Berra, E., Deciphering the emerging role of SUMO conjugation in the hypoxia-signaling cascade (2013) Biol Chem, 394, pp. 459-469
  • Kim, W.Y., Kaelin, W.G., Role of VHL gene mutation in human cancer (2004) J Clin Oncol, 22, pp. 4991-5004
  • Maher, E.R., Kaelin, W.G., Jr., Von Hippel-Lindau disease (1997) Medicine (Baltimore), 76, pp. 381-391
  • Keefe, S.M., Nathanson, K.L., Rathmell, W.K., The molecular biology of renal cell carcinoma (2013) Semin Oncol, 40, pp. 421-428
  • Jonasch, E., Futreal, P.A., Davis, I.J., Bailey, S.T., Kim, W.Y., Brugarolas, J., State of the science: An update on renal cell carcinoma (2012) Mol Cancer Res, 10, pp. 859-880
  • Ohh, M., Park, C.W., Ivan, M., Hoffman, M.A., Kim, T.Y., Huang, L.E., Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein (2000) Nat Cell Biol, 2, pp. 423-427
  • Kaelin, W.G., Jr., The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer (2008) Nat Rev Cancer, 8, pp. 865-873
  • Bae, S.H., Jeong, J.W., Park, J.A., Kim, S.H., Bae, M.K., Choi, S.J., Sumoylation increases HIF-1alpha stability and its transcriptional activity (2004) Biochem Biophys Res Commun, 324, pp. 394-400
  • Cheng, J., Kang, X., Zhang, S., Yeh, E.T., SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia (2007) Cell, 131, pp. 584-595
  • Kim, W.Y., Safran, M., Buckley, M.R., Ebert, B.L., Glickman, J., Bosenberg, M., Failure to prolyl hydroxylate hypoxia-inducible factor alpha phenocopies VHL inactivation in vivo (2006) EMBO J, 25, pp. 4650-4662
  • Cai, Q., Verma, S.C., Kumar, P., Ma, M., Robertson, E.S., Hypoxia inactivates the VHL tumor suppressor through PIASy-mediated SUMO modification (2010) PLoS ONE, 5, p. e9720
  • Chien, W., Lee, K.L., Ding, L.W., Wuensche, P., Kato, H., Doan, N.B., PIAS4 is an activator of hypoxia signalling via VHL suppression during growth of pancreatic cancer cells (2013) Br J Cancer, 109, pp. 1795-1804
  • Rathmell, W.K., Hickey, M.M., Bezman, N.A., Chmielecki, C.A., Carraway, N.C., Simon, M.C., In vitro and in vivo models analyzing von Hippel-Lindau disease-specific mutations (2004) Cancer Res, 64, pp. 8595-8603
  • Rechsteiner, M.P., Von Teichman, A., Nowicka, A., Sulser, T., Schraml, P., Moch, H., VHL gene mutations and their effects on hypoxia inducible factor HIFalpha: Identification of potential driver and passenger mutations (2011) Cancer Res, 71, pp. 5500-5511
  • Hacker, K.E., Lee, C.M., Rathmell, W.K., VHL type 2B mutations retain VBC complex form and function (2008) PLoS ONE, 3, p. e3801
  • Skuli, N., Majmundar, A.J., Krock, B.L., Mesquita, R.C., Mathew, L.K., Quinn, Z.L., Endothelial HIF-2alpha regulates murine pathological angiogenesis and revascularization processes (2012) J Clin Invest, 122, pp. 1427-1443
  • Kang, X., Li, J., Zou, Y., Yi, J., Zhang, H., Cao, M., PIASy stimulates HIF1alpha SUMOylation and negatively regulates HIF1alpha activity in response to hypoxia (2010) Oncogene, 29, pp. 5568-5578
  • Van Hagen, M., Overmeer, R.M., Abolvardi, S.S., Vertegaal, A.C., RNF4 and VHL regulate the proteasomal degradation of SUMO-conjugated Hypoxia-Inducible Factor-2alpha (2010) Nucleic Acids Res, 38, pp. 1922-1931
  • Cimarosti, H., Lindberg, C., Bomholt, S.F., Ronn, L.C., Henley, J.M., Increased protein SUMOylation following focal cerebral ischemia (2008) Neuropharmacology, 54, pp. 280-289
  • Yang, W., Sheng, H., Warner, D.S., Paschen, W., Transient focal cerebral ischemia induces a dramatic activation of small ubiquitin-like modifier conjugation (2008) J Cereb Blood Flow Metab, 28, pp. 892-896
  • Huang, C., Han, Y., Wang, Y., Sun, X., Yan, S., Yeh, E.T., SENP3 is responsible for HIF-1 transactivation under mild oxidative stress via p300 de-SUMOylation (2009) EMBO J, 28, pp. 2748-2762
  • Shan, B., Gerez, J., Haedo, M., Fuertes, M., Theodoropoulou, M., Buchfelder, M., RSUME is implicated in HIF-1-induced VEGF-A production in pituitary tumour cells (2012) Endocr Relat Cancer, 19, pp. 13-27
  • Cerami, E., Gao, J., Dogrusoz, U., Gross, B.E., Sumer, S.O., Aksoy, B.A., The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data (2012) Cancer Discov, 2, pp. 401-404
  • Gao, J., Aksoy, B.A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S.O., Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal (2013) Sci Signal, 6, p. 11
  • Comprehensive molecular characterization of clear cell renal cell carcinoma (2013) Nature, 499, pp. 43-49. , Cancer Genome Atlas Research Network
  • Hoffman, M.A., Ohh, M., Yang, H., Klco, J.M., Ivan, M., Kaelin, W.G., Jr., Von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF (2001) Hum Mol Genet, 10, pp. 1019-1027
  • Knauth, K., Bex, C., Jemth, P., Buchberger, A., Renal cell carcinoma risk in type 2 von Hippel-Lindau disease correlates with defects in pVHL stability and HIF-1alpha interactions (2006) Oncogene, 25, pp. 370-377
  • Semenza, G.L., HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations (2013) J Clin Invest, 123, pp. 3664-3671
  • Knauth, K., Cartwright, E., Freund, S., Bycroft, M., Buchberger, A., VHL mutations linked to type 2C von Hippel-Lindau disease cause extensive structural perturbations in pVHL (2009) J Biol Chem, 284, pp. 10514-10522
  • Rathmell, W.K., Godley, P.A., Recent updates in renal cell carcinoma (2010) Curr Opin Oncol, 22, pp. 250-256
  • Cowey, C.L., Rathmell, W.K., VHL gene mutations in renal cell carcinoma: Role as a biomarker of disease outcome and drug efficacy (2009) Curr Oncol Rep, 11, pp. 94-101
  • Brooks, S.A., Brannon, A.R., Parker, J.S., Fisher, J.C., Sen, O., Kattan, M.W., ClearCode34: A prognostic risk predictor for localized clear cell renal cell carcinoma (2014) Eur Urol, 66, pp. 77-84
  • Gnarra, J.R., Zhou, S., Merrill, M.J., Wagner, J.R., Krumm, A., Papavassiliou, E., Posttranscriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene (1996) Proc Natl Acad Sci USA, 93, pp. 10589-10594
  • Iliopoulos, O., Kibel, A., Gray, S., Kaelin, W.G., Jr., Tumour suppression by the human von Hippel-Lindau gene product (1995) Nat Med, 1, pp. 822-826
  • Zimmer, M., Doucette, D., Siddiqui, N., Iliopoulos, O., Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL-/-tumors (2004) Mol Cancer Res, 2, pp. 89-95
  • Maranchie, J.K., Vasselli, J.R., Riss, J., Bonifacino, J.S., Linehan, W.M., Klausner, R.D., The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma (2002) Cancer Cell, 1, pp. 247-255
  • Richard, D.E., Berra, E., Pouyssegur, J., Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells (2000) J Biol Chem, 275, pp. 26765-26771
  • Tanos, T., Marinissen, M.J., Leskow, F.C., Hochbaum, D., Martinetto, H., Gutkind, J.S., Phosphorylation of c-Fos by members of the p38 MAPK family. Role in the AP-1 response to UV light (2005) J Biol Chem, 280, pp. 18842-18852
  • Groulx, I., Lee, S., Oxygen-dependent ubiquitination and degradation of hypoxiainducible factor requires nuclear-cytoplasmic trafficking of the von Hippel-Lindau tumor suppressor protein (2002) Mol Cell Biol, 22, pp. 5319-5336
  • Safran, M., Kim, W.Y., O'Connell, F., Flippin, L., Gunzler, V., Horner, J.W., Mouse model for noninvasive imaging of HIF prolyl hydroxylase activity: Assessment of an oral agent that stimulates erythropoietin production (2006) Proc Natl Acad Sci USA, 103, pp. 105-110
  • Kondo, K., Klco, J., Nakamura, E., Lechpammer, M., Kaelin, W.G., Jr., Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein (2002) Cancer Cell, 1, pp. 237-246
  • Post, D.E., Van Meir, E.G., Generation of bidirectional hypoxia/HIF-responsive expression vectors to target gene expression to hypoxic cells (2001) Gene Ther, 8, pp. 1801-1807
  • Schoenfeld, A.R., Davidowitz, E.J., Burk, R.D., Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products (2000) Proc Natl Acad Sci USA, 97, pp. 8507-8512
  • Desterro, J.M., Rodriguez, M.S., Hay, R.T., SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation (1998) Mol Cell, 2, pp. 233-239
  • Tatham, M.H., Jaffray, E., Vaughan, O.A., Desterro, J.M., Botting, C.H., Naismith, J.H., Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9 (2001) J Biol Chem, 276, pp. 35368-35374
  • Rodriguez, M.S., Dargemont, C., Hay, R.T., SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting (2001) J Biol Chem, 276, pp. 12654-12659
  • Juengel, E., Engler, J., Natsheh, I., Jones, J., Mickuckyte, A., Hudak, L., Combining the receptor tyrosine kinase inhibitor AEE788 and the mammalian target of rapamycin (mTOR) inhibitor RAD001 strongly inhibits adhesion and growth of renal cell carcinoma cells (2009) BMC Cancer, 9, p. 161
  • Lolkema, M.P., Gervais, M.L., Snijckers, C.M., Hill, R.P., Giles, R.H., Voest, E.E., Tumor suppression by the von Hippel-Lindau protein requires phosphorylation of the acidic domain (2005) J Biol Chem, 280, pp. 22205-22211
  • Castro, C.P., Giacomini, D., Nagashima, A.C., Onofri, C., Graciarena, M., Kobayashi, K., Reduced expression of the cytokine transducer gp130 inhibits hormone secretion, cell growth, and tumor development of pituitary lactosomatotrophic GH3 cells (2003) Endocrinology, 144, pp. 693-700
  • Paez-Pereda, M., Giacomini, D., Refojo, D., Nagashima, A.C., Hopfner, U., Grubler, Y., Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk (2003) Proc Natl Acad Sci USA, 100, pp. 1034-1039
  • Huang, J., Zhao, Q., Mooney, S.M., Lee, F.S., Sequence determinants in hypoxiainducible factor-1alpha for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3 (2002) J Biol Chem, 277, pp. 39792-39800
  • Cockman, M.E., Masson, N., Mole, D.R., Jaakkola, P., Chang, G.W., Clifford, S.C., Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein (2000) J Biol Chem, 275, pp. 25733-25741

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