Abnormality of sugar/amino acid transport and ATP sensor in renal carcinogenesis

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It has been reported that the product of Tsc2 gene, which is the causative gene for the hereditary renal carcinoma (RC) of the Eker rat, functions in nutrient- and/or energy-regulated signal transduction. We found that the product of Bhd gene, which is the causative gene for the hereditary RC of the Nihon rat, shows partial amino acid sequence similarity with the LST7 product of Saccharomyces cerevisiae in amino-terminal half. Yeast mutants of LST7 gene have been reported to show defects in membrane transport system. We found that LST7-disruptant yeasts were slightly more sensitive to rapamycin than wild-type yeasts. However no apparent difference was observed in degree of resistance against toxic amino acid analogues tested so far. Introduction of rat wild-type or carboxy-terminally truncated folliculin-expression plasmids into mutant yeasts did not restore normal rapamycin sensitivity. We are analyzing other phenotypes of LST7 mutant and effect of mammalian folliculin expression in m … More utant yeasts. For analyze folliculin function using mammalian cells, we established and analyzed Bhd deficient renal tumor cell lines (1B series) in which rat Bhd cDNA was expressed by using the tet-off system. Compared with control cells (1R series) introduced with empty vector, 1B cells exhibited no apparent growth suppression. Expression of transpoters such as Gluts did not significantly change. However, 1B and 1R cells showed different morphological phenotypes. At phase-contrast microscopic level, cell adhesion and spreading were differ each other. By co-immunoprecipitation assay, we preliminarily found that the non-muscle myosin was co-precipitated using anti-Bhd antibody in 1B cell-specific manner. One plausible hypothesis is that Bhd products regulates cytoskeletal components as well as membrane transport systems. Through such functions, Bhd may modulates nutrient- or energy-regulated signal transuduction. We will clarify the function of Bhd product and its relation with nutrient/energy-regulated signals as well as Tsc2 product. Less