Franklin J Lee, Keeton Adam B, Bortoff Katherine D, Messina Joseph L
Int J Clin Exp Med. 2008;1(1):89-97. Epub 2008 Jan 25.
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.
胰岛素通过特异性结合并激活酪氨酸激酶胰岛素受体来调节肝源性细胞的代谢和生长。胰岛素诱导的细胞内信号传导通过多种途径进行，包括丝裂原活化蛋白激酶（MEK/ERK）和磷脂酰肌醇3-激酶（PI3K）途径，这些途径进而激活多种下游信号分子。通过筛选发现热休克蛋白60（HSP60；伴侣蛋白60kD）在大鼠肝癌细胞中受胰岛素调节。热休克蛋白是一类分子伴侣，其主要细胞功能是介导新合成蛋白质的正确折叠。细胞对应激的反应特征是蛋白质合成总体减少，以及包括HSP60在内的热休克蛋白家族上调。HSP60在许多疾病和对缺氧的反应中都有作用。本研究旨在探讨胰岛素是否刺激HSP60基因表达。在大鼠H4IIE肝癌细胞中测量了HSP60转录速率和mRNA积累，胰岛素诱导的HSP60表达主要通过MEK/ERK途径。对p38和PI3K途径的抑制表明，其他胰岛素、细胞应激源和细胞因子调节途径对MEK/ERK信号在胰岛素调节HSP60基因表达中的主要作用存在复杂的反馈相互作用。
