Cytoplasmic Polyadenylation Element Binding Protein Deficiency Stimulates PTEN and Stat3 mRNA Translation and Induces Hepatic Insulin Resistance

Ilya M Alexandrov,Yen-Tsung Huang,Maria Ivshina,Joel D Richter,Mei Xu,Rita Bortell,Randall Friedline,Dae Young Jung,Fumihiko Urano,Bryan O'Sullivan-Murphy,Jason K Kim,Hwi Jin Ko,Wataru Ogawa

doi:10.1371/journal.pgen.1002457

Abstract

The cytoplasmic polyadenylation element binding protein CPEB1 (CPEB) regulates germ cell development, synaptic plasticity, and cellular senescence. A microarray analysis of mRNAs regulated by CPEB unexpectedly showed that several encoded proteins are involved in insulin signaling. An investigation of Cpeb1 knockout mice revealed that the expression of two particular negative regulators of insulin action, PTEN and Stat3, were aberrantly increased. Insulin signaling to Akt was attenuated in livers of CPEB–deficient mice, suggesting that they might be defective in regulating glucose homeostasis. Indeed, when the Cpeb1 knockout mice were fed a high-fat diet, their livers became insulin-resistant. Analysis of HepG2 cells, a human liver cell line, depleted of CPEB demonstrated that this protein directly regulates the translation of PTEN and Stat3 mRNAs. Our results show that CPEB regulated translation is a key process involved in insulin signaling.

Highlights

The maintenance of glucose homeostasis requires that organisms respond to changing environmental conditions by balancing pancreatic insulin secretion with the ability of tissues, liver, muscle, and fat, to respond to hormone-induced signaling by importing or secreting glucose [1,2]
We suspected that additional mRNAs whose translation is controlled by CPEB would be involved in senescence; to identify them, we performed microarray analysis of mRNAs associated with polysomes in wild type (WT) and Cpeb1 KO mouse embryo fibroblasts (MEFs) (Figure 1; Table S1)
We noticed that several aberrantly translated mRNAs encoded proteins involved in insulin signaling, which surprisingly suggested that this signal transduction pathway and perhaps glucose metabolism might be compromised in Cpeb1 KO mice

Summary

Introduction

The maintenance of glucose homeostasis requires that organisms respond to changing environmental conditions by balancing pancreatic insulin secretion with the ability of tissues, liver, muscle, and fat, to respond to hormone-induced signaling by importing or secreting glucose [1,2]. Obesity and other insults that promote diabetes do so by causing inflammation and insulin resistance, which is characterized by the inability of tissues to transduce insulin/insulin receptor interactions into elevated glucose uptake in muscle and adipose tissue and/or efficient insulin-mediated suppression of gluconeogenesis in liver In peripheral tissues such as those noted above, insulin association with the insulin receptor (InsR; NM_010568.2) induces insulin receptor substrates (IRS1/2; NM_010570/NM_001081212.1) tyrosine phosphorylation, which through activated PI3-kinase, promotes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to yield phosphatidylinositol (3,4,5)-trisphosphate (PIP3). CPEB-induced stimulated (i.e., deprepressed) translation is initiated when CPEB is phosphorylated on S174 or T171 (speciesdependent), which expels PARN from the ribonucleoprotein complex This event allows Gld to polyadenylate the RNA by

Author Summary

Results

Discussion

Materials and Methods