ELONGIN C: FUNCTION AND ROLE IN VHL DISEASE

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Several lines of evidence indicate that Elongin C, a regulatory subunit of the Elongin transcription factor, plays an essential role, unrelated to transcription, in the tumor suppression function of the von Hippel-Landau protein (VHL). The overall objective of this proposal is to determine the biological function(s) of Elongin C and its role in VHL tumor suppression. We have identified the yeast homologue of Elongin C. Our rationale is that Elongin C function will be conserved in mammalian cells. Our preliminary data indicate that yeast Elongin C interacts strongly and specifically with 4 yeast proteins: Snf4, Yap4, Yap6 and Mdj1. Notably each of these Elongin C binding partners has a mammalian homologue and can be linked to specific stress responses. Thus our hypothesis is that Elongin C is a key protein in the stress response. This hypothesis will be examined as described in the following specific aims. Specific Aim 1. To characterize yeast Elongin C during the stress response. Preliminary studies indicate that the yeast Elongin C gene is non-essential, expressed at low levels during normal cell growth and that the protein is present in both the nucleus and in the cytoplasm. Experiments are described to assess the effects of hypoxic, nutrient, and oxidant stress in Elongin c null strains. Specific Aim 2. To examine the nature and significance of the Elongin C interactions with Snf4, Yap4, Yap6 and Mdj1. Snf4 is the homologue of the gamma subunit of mammalian AMP-activated protein kinase (AMPK). The affect of binding of Elongin C to Snf4 on the kinase activity will be assessed. Yap4 and Yap6 are putative transcription factors and Mdj1 is a mitochondrial chaperone. The interaction between these proteins and Elongin C will identify other factors that may operate in parallel or be redundant with Elongin C. A synthetic lethal screen is described to identify other factors that may compensate for absence of Elongin C VHL tumor suppression, the elucidation of the function(s) of Elongin C may lead to the identification of new therapeutic targets for treatment of VHL disease.