Insulin Dependant Gene Expression of Heat Shock Protein 60 in H4IIE Hepatoma Cells.

Insulin regulates metabolism and growth in cells of hepatic origin by specifically binding to and activating the tyrosine kinase insulin receptor. Insulin-induced intracellular signaling is conducted via multiple pathways, including the MAP kinase (MEK/ERK) and the phosphatidylinositol 3-kinase (PI3K) pathways, which in turn activate multiple downstream signaling molecules. Heat shock protein 60 (HSP60; chaperonin 60kD) was selected by screening to be regulated by insulin in rat hepatoma cells. Heat shock proteins are a family of molecular chaperones whose main cellular function is to mediate the proper folding of newly synthesized proteins. The cellular response to stress is characterized by an overall decrease in protein synthesis, and upregulation of the heat shock protein family, including HSP60. A role for HSP60 has been implied in many diseases and in the responses to hypoxia. The present study was designed to ask whether insulin stimulated HSP60 gene expression. The rate of HSP60 transcription and mRNA accumulation were measured in rat H4IIE hepatoma cells and insulin-induced expression of HSP60 was predominantly via the MEK/ERK pathway. Inhibition of the p38 and PI3K pathways suggest complex feedback interactions of other insulin-, cell stressor- and cytokine- regulated pathways on the primary role of the MEK/ERK signaling in the regulation of HSP60 gene expression by insulin.