title: Myocardin-related transcription factor-A promoting neuronal survival against apoptosis induced by hypoxia/ischemia.
abstract: MRTF-A, known as one of the myocardin-related transcription factors, is widely found in newborn rat cortical or hippocampus neurons as well as in adult rat forebrain. Recent studies indicate that MRTF-A elevates SRF-driven transcription and enhances its stimulation by neurotrophic factor (BDNF). However, the mechanism underlying the contribution of the MRTF-A to neuronal survival is not completely understood. In this study, we investigated the effect of MRTF-A on neuronal apoptosis and its underlying mechanism. First of all, our study demonstrated that MRTF-A expression decreased obviously in rats' brains during the early period of cerebral ischemia-reperfusion. In order to estimate the effect of MRTF-A on neuronal apoptosis in vitro, we used an established experimental paradigm in which MRTF-A protected cortical neurons against both hypoxia-trophic deprivation and hydrogen peroxide-induced apoptosis. Obviously, over-expression of wild-type MRTF-A in cortical neurons inhibited apoptosis rate and enhanced anti-apoptotic gene-MCL-1. In contrast, co-expression of MRTF-A and the small interfering RNA of MRTF-A (siRNA) reversed the effect of neuroprotection and the upregulation on MCL-1 expression afforded by MRTF-A. Our study also determined whether the effect of MRTF-A up-regulating on MCL-1 expression is correlated to MRTF-A-enhancing CArG box transcription. The result showed that over-expression of wild-type MRTF-A upregulated the transcription activity of MCL reporter gene via driving the binding-domain CArG box in MCL-1 promoter, which was also reversed by co-expression of MRTF-A siRNA. In addition, we also found that BDNF neuroprotection on apoptosis induced by hypoxia-trophic withdrawal was not only inhibited by LY29004 and PD98059 but also partially blocked by transfection of dominant-negative MRTF-A in cortical neurons via enhancing the expression of anti-apoptotic gene-MCL-1, suggesting a downstream neuroprotective mechanism to BDNF neuroprotection on apoptosis.
authors.affiliation: Department of Pharmacology, Medical College of Wuhan University of Science and Technology, Wuhan 430080, PR China.
authors.forename: Xiao-Lu
authors.initials: XL
authors.lastname: Cao
authors.forename: Xia-Min
authors.initials: XM
authors.lastname: Hu
authors.forename: Jia-Qing
authors.initials: JQ
authors.lastname: Hu
authors.forename: Wen-Xia
authors.initials: WX
authors.lastname: Zheng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D019556:COS Cells; D002470:Cell Survival / Q000235:genetics; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D020925:Hypoxia-Ischemia, Brain / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D014157:Transcription Factors; C557977:myocardin-related transcription factor-A, rat