Valproic acid induces functional heat-shock protein 70 via Class I histone deacetylase inhibition in cortical neurons: a potential role of Sp1 acetylation
| Autor: | Zoya Marinova, De-Maw Chuang, Min-Huei Liang, Yan Leng, Jens R. Wendland, Peter Leeds, Shigeru Yasuda, Ming Ren |
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| Rok vydání: | 2009 |
| Předmět: |
Chromatin Immunoprecipitation
Time Factors Cell Survival Immunoglobulins Tetrazolium Salts Histone Deacetylase 1 Pharmacology Biology Biochemistry Neuroprotection Article Histone Deacetylases Cellular and Molecular Neuroscience chemistry.chemical_compound medicine Animals Drug Interactions HSP70 Heat-Shock Proteins Phosphatidylinositol Enzyme Inhibitors Cells Cultured PI3K/AKT/mTOR pathway Cerebral Cortex Neurons Dose-Response Relationship Drug Valproic Acid Acetylation Sodium butyrate Embryo Mammalian Molecular biology HDAC1 Rats Thiazoles Trichostatin A chemistry lipids (amino acids peptides and proteins) Histone deacetylase Apicidin medicine.drug |
| Zdroj: | Journal of Neurochemistry. 111:976-987 |
| ISSN: | 1471-4159 0022-3042 |
| DOI: | 10.1111/j.1471-4159.2009.06385.x |
| Popis: | Neuroprotective properties of the mood stabilizer valproic acid (VPA) are implicated in its therapeutic efficacy. Heat-shock protein 70 (HSP70) is a molecular chaperone, neuroprotective and anti-inflammatory agent. This study aimed to investigate underlying mechanisms and functional significance of HSP70 induction by VPA in rat cortical neurons. VPA treatment markedly up-regulated HSP70 protein levels, and this was accompanied by increased HSP70 mRNA levels and promoter hyperacetylation and activity. Other HDAC inhibitors – sodium butyrate, trichostatin A, and Class I HDAC-specific inhibitors MS-275 and apicidin, – all mimicked the ability of VPA to induce HSP70. Pre-treatment with phosphatidylinositol 3-kinase inhibitors or an Akt inhibitor attenuated HSP70 induction by VPA and other HDAC inhibitors. VPA treatment increased Sp1 acetylation, and a Sp1 inhibitor, mithramycin, abolished the induction of HSP70 by HDAC inhibitors. Moreover, VPA promoted the association of Sp1 with the histone acetyltransferases p300 and recruitment of p300 to the HSP70 promoter. Further, VPA-induced neuroprotection against glutamate excitotoxicity was prevented by blocking HSP70 induction. Taken together, the data suggest that the phosphatidylinositol 3-kinase/Akt pathway and Sp1 are likely involved in HSP70 induction by HDAC inhibitors, and induction of HSP70 by VPA in cortical neurons may contribute to its neuroprotective and therapeutic effects. |
| Databáze: | OpenAIRE |
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