Insulin signaling pathway protects neuronal cell lines by Sirt3 mediated IRS2 activation
| Autor: | Neha, Mishra, Sonam, Lata, Priyanka, Deshmukh, Kajal, Kamat, Avadhesha, Surolia, Tanushree, Banerjee |
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| Rok vydání: | 2017 |
| Předmět: |
Neurons
Glycogen Synthase Kinase 3 beta Tunicamycin Forkhead Box Protein O3 Protein Deglycase DJ-1 Hydrogen Peroxide Endoplasmic Reticulum Stress Receptor Insulin Mice Oxidative Stress Gene Expression Regulation Antigens CD Cell Line Tumor Sirtuin 3 Insulin Receptor Substrate Proteins Animals Humans Insulin Insulin-Like Growth Factor I Phosphorylation RNA Small Interfering Proto-Oncogene Proteins c-akt Cell Proliferation Signal Transduction |
| Zdroj: | BioFactors (Oxford, England). 44(3) |
| ISSN: | 1872-8081 |
| Popis: | Cellular stress like ER and oxidative stress are the principle causative agents of various proteinopathies. Multifunctional protein PARK7/DJ-1 provides protection against cellular stress. Recently, insulin/IGF also has emerged as a neuro-protective molecule. However, it is not known whether DJ-1 and insulin/IGF complement each other for cellular protection in response to stress. In this study, we show for the first time, that in human and mouse neuronal cell lines, down regulation of DJ-1 for 48 h leads to compensatory upregulation of insulin/IGF signaling (IIS) pathway genes, namely, insulin receptor, insulin receptor substrate, and Akt under normal physiological conditions as well as in cellular stress conditions. Moreover, upon exogenous supply of insulin there is a marked increase in the IIS components both at gene and protein levels leading to down regulation and inactivation of GSK3β. By immunoprecipitation, it was observed that Sirt3 mediated deacetylation and activation of FoxO3a could not occur under DJ-1 downregulation. Transient DJ-1 downregulation also led to Akt mediated increased phosphorylation and nuclear exclusion of FoxO3a. When DJ-1 was downregulated increased interaction of Sirt3 with IRS2 was observed leading to its activation resulting in IIS upregulation. Thus, transient downregulation of DJ-1 leads to stimulation of IIS pathway by Sirt3 mediated IRS2 activation. Consequently, antiapoptotic program is triggered in neuronal cells via Akt-GSK3β-FoxO3a axis. © 2018 BioFactors, 44(3):224-236, 2018. |
| Databáze: | OpenAIRE |
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