Insulin-like growth factor binding protein-1 (IGFBP-1) is a 30 kDa hepatic protein. It is the major short-term modulator of IGF bioavailability and circulating levels of IGFBP-1 are elevated in a variety of clinical disorders where anabolism is impaired, including poorly controlled diabetes mellitus, renal failure, the AIDS wasting syndrome and human aging. Insulin rapidly suppresses hepatic production of IGFBP-1 at the level of gene transcription via insulin response sequences (IRSs) located in the proximal IGFBP-1 promoter. The investigator has reported that signaling, via protein kinase B (PKB) and forehead proteins, plays a critical role in regulating IGFBP-1 gene expression by insulin. Recent studies indicate that mechanisms mediating the effect of insulin on IGFBP-1 promoter activity are evolutionarily conserved suggesting that they are important in mediating effects of related growth factors on cell survival. Hence, IGFBP1 provides an important model for understanding evolutionarily conserved mechanisms mediating effects of insulin-regulated gene expression in the liver, and the effects of related growth factors on other basic cell processes including cell survival. The proposed studies will use recombinant technologies and cell culture models to examine specific mechanisms by which these transcription factors may contribute to the multi-hormonal regulation of IGFBP-1 promoter activity. Studies in cell culture and animal models will determine whether these mechanisms play a critical role in mediating effects of insulin on endogenous gene expression in the liver. Together, these studies will provide new insight into the role that signaling, via PKB and forkhead proteins, plays in mediating effects of insulin on gene expression in the liver, focusing on the regulation of IGFBP-1.
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