Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

IGR_VHL_GE

ABSTRACT: VHL is a tumor suppressor gene involved in the oxygen-sensing pathway whose germline mutations predispose to distinct phenotypes. Heterozygous mutations predispose to von Hippel-Lindau disease characterized by the development of multiple tumors (including hemangioblastomas, renal cell carcinomas and pheochromocytomas)1-3. More recently, a specific VHL-R200W mutation was shown to be responsible for Chuvash Polycythemia in homozygous carriers whereas heterozygous individuals have no clinical manifestation4. We report here a family carrying, on the same allele, VHL mutations characteristics of the two types of disease (a Chuvash polycythemia-R200W mutation and a von Hippel-Lindau disease-R161Q mutation). Genotyping, modeling analysis and functional studies, including transcriptomic profile of the distinct mutants validated for the first time on direct HIF target genes, show a gradual capacity of the VHL mutants to regulate the hypoxia responsive pathway that correlate with the severity of the developed phenotype. Our study provide original results that illuminate genotype/phenotype correlations in von Hippel-Lindau disease.

ORGANISM(S): Homo sapiens

SUBMITTER: JUSTINE GUEGAN

PROVIDER: E-MTAB-1269 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis.

Couvé Sophie S Ladroue Charline C Laine Elodie E Mahtouk Karène K Guégan Justine J Gad Sophie S Le Jeune Hélène H Le Gentil Marion M Nuel Gregory G Kim William Y WY Lecomte Bernard B Pagès Jean-Christophe JC Collin Christine C Lasne Françoise F Benusiglio Patrick R PR Bressac-de Paillerets Brigitte B Feunteun Jean J Lazar Vladimir V Gimenez-Roqueplo Anne-Paule AP Mazure Nathalie M NM Dessen Philippe P Tchertanov Luba L Mole David R DR Kaelin William W Ratcliffe Peter P Richard Stéphane S Gardie Betty B

Cancer research 20141104 22

The classic model of tumor suppression implies that malignant transformation requires full "two-hit" inactivation of a tumor-suppressor gene. However, more recent work in mice has led to the proposal of a "continuum" model that involves more fluid concepts such as gene dosage-sensitivity and tissue specificity. Mutations in the tumor-suppressor gene von Hippel-Lindau (VHL) are associated with a complex spectrum of conditions. Homozygotes or compound heterozygotes for the R200W germline mutation ...[more]

PMID: 25371412

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Project description:Radiotherapy has a critical role in the treatment of small cell lung cancer (SCLC). Effectiveness of radiation in SCLC remains limited as resistance results from defects in apoptosis. In the current study, we investigated whether using a Bcl-2/Bcl-XL inhibitor S44563 can enhance radiosensitivity of SCLC cells in vitro and in vivo. In vitro studies confirmed that S44563 induce apoptosis in SCLC cells by inducing hallmarks of apoptosis (cleaved caspase-3, sub-G1 fraction induction and induction of the mitochondrial caspase activation pathway). S44563 markedly enhanced sensitivity of H146 cells and H69 cells to radiation in clonogenic assay. In addition, the combination S44563 and cisplatin-based chemo-radiation showed a dramatic tumor growth delay and increased overall survival in mouse xenograft models. In vitro experiments demonstrated a greater induction of apoptosis (sub-G1 fraction and cleaved caspase-3) with the combination as well as in vivo caspase-3 immunostaining. This positive interaction between S44563 and radiation was greater when S44563 was given after the completion of the radiation, which may be explained by the radiation-induced over expression of anti-apoptotic proteins (Bcl-2 and Bcl-XL) through the NF-?B pathway activation. Taken together, these data underline the critical role of sequence administration of targeted therapies with conventional therapies. SCLC cells which survive to IR highly rely on the induction of anti apoptotic proteins in part through NF- ?B activation for their survival yielding to the concept of 'contextual oncogene addiction' to the Bcl-2/Bcl-XL pathway providing rational for targeting survival pathways to potentiate IR. For transcriptome analysis, 106 cells were seeded in T25 flasks, allowed to growth for 24 h, and then left untreated or treated with 2 Gy radiation. After 24 hours, cells were harvested, lysed for the extraction of RNA, and processed to analyze gene expression.The design of this study consists to 6 hybridizations in dual color with Agilent Human Genome 4x44K (design 014850). The reference is always the untreated condition.

Dataset Information

IGR_VHL_GE

Publications

Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis.

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