Gene- and activation-specific mechanisms for insulin inhibition of basal and glucocorticoid-induced insulin-like growth factor binding protein-1 and phosphoenolpyruvate carboxykinase transcription. Roles of forkhead and insulin response sequences.
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The insulin response sequence (IRS) of the phosphoenolpyruvate carboxykinase (PEPCK) promoter, located within the glucocorticoid response unit, was first characterized by its ability to mediate insulin inhibition when inserted into a thymidine kinase promoter. The IRSs of the PEPCK and insulin-like growth factor binding protein-1 (IGFBP-1) promoters have been proposed to contribute to regulation by glucocorticoids and insulin. Forkhead (FKHR) recognizes IRS sequences, is phosphorylated in response to insulin, and mediates insulin inhibition of basal IGFBP-1 transcription in an IRS-dependent manner. Here, we investigate the contributions of FKHR and IRSs to insulin inhibition of basal and glucocorticoid-induced transcription of PEPCK and IGFBP-1. Expression of T/S/S, in which three putative protein kinase B (PKB) sites in FKHR are mutated, reduced insulin inhibition of basal expression of IGFBP-1 but not PEPCK. Mutation of the IGFBP-1 IRSs abolished insulin inhibition in the presence of T/S/S. Mutation of the PEPCK IRS had no effect on insulin inhibition in the presence of T/S/S, indicating that insulin inhibits PEPCK transcription independently of the IRS or of the putative PKB phosphorylation sites in FKHR. Mutations in the IRS or FKHR had no effect on insulin inhibition of glucocorticoid-induced transcription of either the PEPCK or IGFBP-1 gene. Thus, insulin uses gene- and activation-specific mechanisms to regulate the basal and glucocorticoid-induced activity of these genes.
author list (cited authors)
Yeagley, D., Guo, S., Unterman, T., & Quinn, P. G.
complete list of authors
Yeagley, D||Guo, S||Unterman, T||Quinn, PG