MOLECULAR BIOLOGY OF GROWTH REGULATION BY NUTRITION

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DESCRIPTION (adapted from the applicant's abstract): Specific alterations in IGF-I, IGF-II and albumin gene expression are observed in animals that are growth-arrested due to nutritional insufficiency. At least part of the reduction in mRNA is post-transcriptional. Studies of nutritional regulation of albumin synthesis will include an analysis of the effect of amino acid restriction on albumin mRNA stability. Other experiments will involve site-directed mutagenesis of a cloned full-length albumin cDNA, to test the hypothesis that the defect leading to decreased albumin mRNA abundance in amino acid-restricted cells in impaired translation of albumin mRNA. Additionally, regulation of albumin gene expression by protein restriction in intact animals will be studied in Nagase analbuminemic rats and in transgenic mice expressing an albumin minigene or mutant constructs of the albumin minigene. Studies of the nutritional regulation of IGF-II synthesis will include analysis of the effects of amino acid restriction of IGF-II mRNA stability, and identification of sequences in the 3'-untranslated region of IGF-II mRNA which are involved in its regulation by amino acid availability. The normal pathway for IGF- II mRNA degradation will be compared with the pathway utilized in amino acid-restricted cells. The effect of amino acid restriction of IGF-I mRNA abundance and gene transcription will be studied in cultured rat hepatocytes. It will be determined if sequences in the long 3'- untranslated region of the 8 kb species of IGF-I mRNA are involved in its regulation in amino acid-restricted cultured cells.