Arlot Group Research

The Von Hippel Lindau (VHL) disease is a rare autosomal-dominant hereditary neoplastic disease associated with germline loss-of-function mutations of the VHL gene. Patients affected by the VHL disease may develop both benign and malignant tumors including clear-cell renal cell carcinoma (ccRCC), retinal angioma, cerebellar and spinal hemangioblastoma, pheochromocytoma and pancreatic cancers. We investigate the functions of VHL in the process of tumorigenesis.  The vhl gene product (pVHL) is involved in multiple biological processes such as cell growth, differentiation, cell motility and response to hypoxia. The vhl gene is located at position 3p25.3and  encodes two transcripts. The mRNA variant 1 encodes two protein isoforms, pVHL213 and pVHL160, that have been extensively documented in the literature. Variant 2 is produced by alternative splicing of exon 2 and encodes a pVHL isoform of 172 amino acids (pVHL172). Detection of both mRNA variants in human cells and tumor tissues (kidney, breast) shows varying ratios (our unpublished data). A higher relative expression of the variant 2-to-variant 1 is sometimes evidenced in tumors and it is interestingly associated with a lower prognostic, suggesting that an imbalance in the expression of the different pVHL isoforms may be crucial in cell malignant transformation.  The variant 1 is translated into two protein isoforms, pVHL213 and pVHL160, that have been extensively documented in the literature. Variant 2 is produced by alternative splicing of exon 2 and encodes a pVHL isoform of 172 amino acids with a theoretical molecular weight of 19 kDa (pVHL172).

Our project 
*  To identify specific pVHL172 interacting proteins and functions
** To understand the molecular and cellular mechanisms underlying the functions of the pVHL isoforms in cells and induced tumors as well as the impact of uncharacterized VHL mutations on its function(s)
***To unravel the regulatory mechanisms driving the alternative splicing of the VHL pre-mRNA (sequences and associated proteins) leading to pVHL172 expression

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