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A SUMOylation-defec...
A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma
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Bertolotto, Corine (author)
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Lesueur, Fabienne (author)
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Giuliano, Sandy (author)
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show more...
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Strub, Thomas (author)
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de Lichy, Mahaut (author)
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Bille, Karine (author)
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Dessen, Philippe (author)
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d'Hayer, Benoit (author)
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Mohamdi, Hamida (author)
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Remenieras, Audrey (author)
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Maubec, Eve (author)
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de la Fouchardiere, Arnaud (author)
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Molinie, Vincent (author)
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Vabres, Pierre (author)
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Dalle, Stephane (author)
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Poulalhon, Nicolas (author)
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Martin-Denavit, Tanguy (author)
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Thomas, Luc (author)
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Andry-Benzaquen, Pascale (author)
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Dupin, Nicolas (author)
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Boitier, Francoise (author)
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Rossi, Annick (author)
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Perrot, Jean-Luc (author)
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Labeille, Bruno (author)
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Robert, Caroline (author)
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Escudier, Bernard (author)
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Caron, Olivier (author)
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Brugieres, Laurence (author)
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Saule, Simon (author)
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Gardie, Betty (author)
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Gad, Sophie (author)
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Richard, Stephane (author)
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Couturier, Jerome (author)
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Teh, Bin Tean (author)
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Ghiorzo, Paola (author)
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Pastorino, Lorenza (author)
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Puig, Susana (author)
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Badenas, Celia (author)
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- Olsson, Håkan (author)
- Lund University,Lunds universitet,Medicinsk onkologi,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Medical oncology,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Ingvar, Christian (author)
- Lund University,Lunds universitet,Kirurgi, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Surgery (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine
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Rouleau, Etienne (author)
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Lidereau, Rosette (author)
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Bahadoran, Philippe (author)
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Vielh, Philippe (author)
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Corda, Eve (author)
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Blanche, Helene (author)
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Zelenika, Diana (author)
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Galan, Pilar (author)
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Chaudru, Valerie (author)
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Lenoir, Gilbert M. (author)
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Lathrop, Mark (author)
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Davidson, Irwin (author)
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Avril, Marie-Francoise (author)
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Demenais, Florence (author)
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Ballotti, Robert (author)
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Bressac-de Paillerets, Brigitte (author)
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(creator_code:org_t)
- 2011-10-19
- 2011
- English.
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 480:7375, s. 94-98
- Related links:
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http://dx.doi.org/10...
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Abstract
Subject headings
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- So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes(1); risk factors associated with RCC include smoking, obesity and hypertension(2). A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers(3). The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene(4); it also stimulates the transcription of hypoxia inducible factor(5) (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes(6). We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (Psi KXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kirurgi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Surgery (hsv//eng)
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- By the author/editor
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Bertolotto, Cori ...
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Lesueur, Fabienn ...
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Giuliano, Sandy
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Strub, Thomas
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de Lichy, Mahaut
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Bille, Karine
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show more...
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Dessen, Philippe
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d'Hayer, Benoit
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Mohamdi, Hamida
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Remenieras, Audr ...
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Maubec, Eve
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de la Fouchardie ...
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Molinie, Vincent
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Vabres, Pierre
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Dalle, Stephane
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Poulalhon, Nicol ...
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Martin-Denavit, ...
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Thomas, Luc
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Andry-Benzaquen, ...
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Dupin, Nicolas
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Boitier, Francoi ...
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Rossi, Annick
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Perrot, Jean-Luc
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Labeille, Bruno
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Robert, Caroline
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Escudier, Bernar ...
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Caron, Olivier
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Brugieres, Laure ...
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Saule, Simon
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Gardie, Betty
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Gad, Sophie
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Richard, Stephan ...
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Couturier, Jerom ...
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Teh, Bin Tean
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Ghiorzo, Paola
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Pastorino, Loren ...
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Puig, Susana
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Badenas, Celia
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Olsson, Håkan
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Ingvar, Christia ...
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Rouleau, Etienne
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Lidereau, Rosett ...
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Bahadoran, Phili ...
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Vielh, Philippe
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Corda, Eve
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Blanche, Helene
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Zelenika, Diana
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Galan, Pilar
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Chaudru, Valerie
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Lenoir, Gilbert ...
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Lathrop, Mark
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Davidson, Irwin
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Avril, Marie-Fra ...
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Demenais, Floren ...
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Ballotti, Robert
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Bressac-de Paill ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Surgery
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Nature
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Lund University