p38 Mitogen-activated Protein Kinase-dependent Regulation of SRC-3 and Involvement in Retinoic Acid Receptor α Signaling in Embryonic Cortical Neurons

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 RAR alpha to retinoic acid responsive element (RARE) was rapidly increased in neurons following ATRA treatment. Inhibition of p38 MAPK significantly enhanced the RAR alpha-RARE binding activity, but had no effects on ATRA-induced decrease of RAR alpha. 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 RAR alpha-mediated signaling in developing neurons. (C) 2009 IUBMB IUBMB Life, 61(6): 670-678, 2009