Insulin-like growth factor-I (IGF-I) is an important anabolic factor with broad roles in cellular growth and tissue function. Circulating IGF-I is produced by the liver, where it is regulated at the level of gene transcription by insulin and nutritional status. Although the IGF- I gene is complex, most transcripts are initiated in exon 1; regulation by insulin appears to involve """"""""footprint region V"""""""" downstream from the major initiation sites in exon 1. The logical next step is to characterize the nuclear factors that interact with region V to confer regulation by insulin. The Emory group has identified a novel transcription factor, """"""""c52,"""""""" that appears to be involved in the control of IGF-I expression. c52 exhibits insulin-responsive expression, can bind to IGF-I region V in vitro, and can stimulate the expression of an IGF-I region V reporter construct in vivo. We will test the involvement of c52 in regulated IGF-I expression by asking four critical questions: (a) where does c52 interact with IGF-I region V?; (b) is c52 action on IGF-I expression modulated by insulin or amino acids?; (c) is c52 required for insulin-related regulation of IGF-I transcription?; and (d) does c52 interact with Sp1, another transcription factor involved with region V? These studies should yield important new knowledge related to diabetes pathophysiology, and provide the Trainee with the background in modern molecular biology and cellular physiology needed to pursue a career as an independent investigator.
|Kaytor, E N; Zhu, J L; Pao, C I et al. (2001) Physiological concentrations of insulin promote binding of nuclear proteins to the insulin-like growth factor I gene. Endocrinology 142:1041-9|
|Kaytor, E N; Zhu, J L; Pao, C I et al. (2001) Insulin-responsive nuclear proteins facilitate Sp1 interactions with the insulin-like growth factor-I gene. J Biol Chem 276:36896-901|