title: p38 mitogen-activated protein kinase-dependent regulation of SRC-3 and involvement in retinoic acid receptor alpha signaling in embryonic cortical neurons.
abstract: Appropriate retinoic acid (RA) signaling is essential in the development of the central nervous system (CNS). Previous studies have shown that RA activates p38 mitogen-activated protein kinase (MAPK) and steroid receptor coactivator (SRC)-3 in tumor cells in vitro. It is unknown whether the activation of p38 MAPK and SRC-3 is involved in RA-mediated CNS development. The current study investigated a possible role for p38 MAPK in the regulation of (SRC)-3 phosphorylation/degradation and in retinoic acid receptor (RAR)alpha signaling in mouse fetal cortical neurons treated with all-trans retinoic acid (ATRA). Results showed that ATRA treatment rapidly activated p38 MAPK, which in turn resulted in phosphorylation with subsequent degradation of SRC-3. Inhibition of p38 MAPK by SB203580 blocked the phosphorylation and degradation of SRC-3. The binding of RARalpha to retinoic acid responsive element (RARE) was rapidly increased in neurons following ATRA treatment. Inhibition of p38 MAPK significantly enhanced the RARalpha-RARE binding activity, but had no effects on ATRA-induced decrease of RARalpha. Treatment of the fetal cortical neurons with ATRA significantly increased the expression of HOXd3, a retinoid-target gene. The increase of HOXd3 expression was augmented when p38 MAPK activity was inhibited by a specific inhibitor, SB203580. Results suggest that ATRA activates the p38 MAPK signal pathway with resultant degradation of SRC-3, and that p38 MAPK is involved in the regulation of RARalpha-mediated signaling in developing neurons.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chai
authors.forename: Lihong
authors.initials: L
authors.lastname: Yang
authors.forename: Baofeng
authors.initials: B
authors.lastname: Yu
authors.forename: Quanren
authors.initials: Q
authors.lastname: He
authors.forename: Wan-I
authors.initials: WI
authors.lastname: Li
authors.forename: Ran
authors.initials: R
authors.lastname: Zhou
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zheng
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D051548:Histone Acetyltransferases / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000187:drug effects; D056921:Nuclear Receptor Coactivator 3; D010766:Phosphorylation; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C484113:Hoxd3 protein, mouse; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D015534:Trans-Activators; D014212:Tretinoin; D051548:Histone Acetyltransferases; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3; D048051:p38 Mitogen-Activated Protein Kinases