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Les séminaires de l'IGDR ont lieu,
sauf avis contraire,
sur le campus santé à Villejean
dans le bâtiment 13,
les vendredis de 12h30 à 13h30
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Mai 2012
Vendredi 25 Mai Brigitte BRESSAC DE PAILLERETS,
Service de Génétique IGR, Inserm U946, Paris
A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma
Invité(e) par Marie-dominique Galibert-anne
Résumé : 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; risk factors associated with RCC include smoking, obesity and hypertension. A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers. The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene; it also stimulates the transcription of hypoxia inducible factor (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes. We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. We identify 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 (YKXE) 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.
Juin 2012
Vendredi 01 Juin Alan WARREN,
MRC Laboratory of Molecular Biology, Cambridge, UK
Bad blood between ribosomal subunits
Invité(e) par Reynald Gillet
Résumé : Ribosome assembly is an essential, highly conserved process that is tightly coupled to cell growth and proliferation. However, the molecular mechanism underlying this process remains poorly understood. Excitingly, a new class of cancer predisposition syndromes collectively called the “ribosomopathies” has recently emerged that harbour mutations in components of the ribosome assembly pathway. In particular, we have discovered that the SBDS protein that is deficient in the leukaemia predisposition disorder Shwachman-Diamond syndrome is required for maturation of the large ribosomal subunit. SBDS controls the translational activation of ribosomes by catalysing dissociation of the anti-association factor eIF6 from nascent 60S subunits, but the precise mechanism remains unclear. We propose a model in which GTP-dependent conformational change in elongation factor-like 1 (EFL1) triggers an inter-domain rotation in SBDS that directly or indirectly triggers eIF6 release. We are currently testing this hypothesis at the molecular level by combining cryo-electron microscopy, NMR spectroscopy and X-ray crystallography with biochemistry and innovative genetic platforms.
Our long-term goal is to elucidate the molecular mechanism of eukaryotic ribosome assembly and to elucidate the pathways involved in the surveillance of ribosome integrity. In particular, dissociation of the anti-association factor eIF6 is a critical step in the maturation of the large ribosomal subunit that allows assembly of actively translating ribosomes. Surprisingly, we have recently shown that defective eIF6 release from nascent 60S ribosomal subunits is fundamental to the pathophysiology of the leukaemia predisposition disorder Shwachman-Diamond syndrome (SDS), caused by deficiency of the SBDS protein.
Using a multidisciplinary approach combining structural, biochemical and genetic approaches in a variety of model systems, we are testing the hypothesis that SBDS is an adaptor that couples GTP hydrolysis by elongation factor-like 1 on the ribosome to the release of eIF6 from the 60S intersubunit interface by a conformational coupling mechanism. In addition, we are using the power of Drosphila genetics to elucidate the stress signalling pathways that are activated by defective late 60S maturation in higher eukaryotes.
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