title: Role of megakaryoblastic acute leukemia-1 in ERK1/2-dependent stimulation of serum response factor-driven transcription by BDNF or increased synaptic activity.
abstract: Serum response factor (SRF)-mediated transcription contributes to developmental and adult brain plasticity. Therefore, we investigated the role of a newly identified SRF coactivator, MKL1, in the regulation of SRF-driven transcription in rat forebrain neurons. MKL1 expression was found in newborn rat cortical or hippocampal neurons in culture as well as in adult rat forebrain. Immunostaining demonstrated constitutive nuclear localization of MKL1 in the CA1 region of the hippocampus, in the deep layers of the neocortex, and in cultured neurons. Overexpression of MKL1 in primary cortical neurons elevated SRF-driven transcription and enhanced its stimulation by BDNF. In addition, inhibition of endogenous MKL1 by overexpression of a dominant-negative MKL1 mutant or by small interfering RNA reduced BDNF activation of SRF-driven transcription. In neurons, endogenous MKL1 was associated with SRF-regulated chromatin regions of several endogenous genes including c-fos, JunB, Srf, and Cyr61. BDNF activation of MKL1/SRF-driven transcription was dependent on the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, which also led to MKL1 phosphorylation. Finally, synaptic activity stimulation of SRF-driven transcription was reduced by inhibition of endogenous MKL1. Conversely, synaptic activity enhanced transcription by overexpressed MKL1. MKL1 regulation by synaptic activity was mediated through the NMDA receptor-activated ERK1/2. These results suggest that neuronal MKL1 contributes to SRF-regulated gene expression induced by BDNF or synaptic activity. In addition, MKL1 appears as a novel mediator of the signaling between ERK1/2 and SRF. Moreover, MKL1 is a likely regulator of SRF-driven transcription programs that underlie neuronal plasticity.
authors.affiliation: Kentucky Spinal Cord Injury Research Center and Department of Neurological Surgery, University of Louisville, Louisville, Kentucky 40292, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kalita
authors.forename: Giorgi
authors.initials: G
authors.lastname: Kharebava
authors.forename: Jing-Juan
authors.initials: JJ
authors.lastname: Zheng
authors.forename: Michal
authors.initials: M
authors.lastname: Hetman
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D002070:Butadienes / Q000494:pharmacology; D019556:COS Cells; D002478:Cells, Cultured / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D002522:Chlorocebus aethiops; D002867:Chromones / Q000494:pharmacology; D055515:Cysteine-Rich Protein 61; D005786:Gene Expression Regulation / Q000502:physiology*; D016762:Genes, fos; D006624:Hippocampus / Q000166:cytology; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000737:chemistry / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D016548:Prosencephalon / Q000166:cytology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D026362:Serum Response Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D014162:Transfection
chemical_list: D000577:Amides; D019208:Brain-Derived Neurotrophic Factor; D002070:Butadienes; C501849:CCN1 protein, rat; D002867:Chromones; D055515:Cysteine-Rich Protein 61; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009025:Morpholines; D009570:Nitriles; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011725:Pyridines; D026362:Serum Response Factor; D014157:Transcription Factors; C113580:U 0126; C108830:Y 27632; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D016202:N-Methylaspartate; D011189:Potassium Chloride; D015761:4-Aminopyridine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D001640:Bicuculline