PMID- 30244496 OWN - NLM STAT- MEDLINE DCOM- 20191028 LR - 20191028 IS - 1471-4159 (Electronic) IS - 0022-3042 (Linking) VI - 148 IP - 2 DP - 2019 Jan TI - Involvement of SRF coactivator MKL2 in BDNF-mediated activation of the synaptic activity-responsive element in the Arc gene. PG - 204-218 LID - 10.1111/jnc.14596 [doi] AB - The expression of immediate early genes (IEGs) is thought to be an essential molecular basis of neuronal plasticity for higher brain function. Many IEGs contain serum response element in their transcriptional regulatory regions and their expression is controlled by serum response factor (SRF). SRF is known to play a role in concert with transcriptional cofactors. However, little is known about how SRF cofactors regulate IEG expression during the process of neuronal plasticity. We hypothesized that one of the SRF-regulated neuronal IEGs, activity-regulated cytoskeleton-associated protein (Arc; also termed Arg3.1), is regulated by an SRF coactivator, megakaryoblastic leukemia (MKL). To test this hypothesis, we initially investigated which binding site of the transcription factor or SRF cofactor contributes to brain-derived neurotrophic factor (BDNF)-induced Arc gene transcription in cultured cortical neurons using transfection and reporter assays. We found that BDNF caused robust induction of Arc gene transcription through a cAMP response element, binding site of myocyte enhancer factor 2, and binding site of SRF in an Arc enhancer, the synaptic activity-responsive element (SARE). Regardless of the requirement for the SRF-binding site, the binding site of a ternary complex factor, another SRF cofactor, did not affect BDNF-mediated Arc gene transcription. In contrast, chromatin immunoprecipitation revealed occupation of MKL at the SARE. Furthermore, knockdown of MKL2, but not MKL1, significantly decreased BDNF-mediated activation of the SARE. Taken together, these findings suggest a novel mechanism by which MKL2 controls the Arc SARE in response to BDNF stimulation. CI - (c) 2018 International Society for Neurochemistry. FAU - Kikuchi, Keietsu AU - Kikuchi K AD - Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. FAU - Ihara, Daisuke AU - Ihara D AD - Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. FAU - Fukuchi, Mamoru AU - Fukuchi M AD - Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. FAU - Tanabe, Hiroki AU - Tanabe H AD - Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. FAU - Ishibashi, Yuta AU - Ishibashi Y AD - Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. FAU - Tsujii, Junya AU - Tsujii J AD - Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. FAU - Tsuda, Masaaki AU - Tsuda M AD - Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. FAU - Kaneda, Marisa AU - Kaneda M AD - Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. FAU - Sakagami, Hiroyuki AU - Sakagami H AD - Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan. FAU - Okuno, Hiroyuki AU - Okuno H AD - Department of Biochemistry and Molecular Biology, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan. FAU - Bito, Haruhiko AU - Bito H AUID- ORCID: 0000-0001-6315-9594 AD - Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. FAU - Yamazaki, Yuya AU - Yamazaki Y AD - Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. FAU - Ishikawa, Mitsuru AU - Ishikawa M AD - Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. FAU - Tabuchi, Akiko AU - Tabuchi A AUID- ORCID: 0000-0001-8168-3410 AD - Laboratory of Molecular Neurobiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181112 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cytoskeletal Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (Serum Response Factor) RN - 0 (Transcription Factors) RN - 0 (activity regulated cytoskeletal-associated protein) RN - 0 (myocardin-related transcription factor-B, rat) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism/pharmacology MH - Cytoskeletal Proteins/*biosynthesis/genetics MH - Female MH - Nerve Tissue Proteins/*biosynthesis/genetics MH - Neurons/drug effects/*physiology MH - Rats MH - Rats, Sprague-Dawley MH - Serum Response Factor/genetics/metabolism MH - Transcription Factors/*metabolism MH - Transcriptional Activation/drug effects/*physiology OTO - NOTNLM OT - Arc OT - BDNF OT - MKL OT - SARE OT - SRF OT - TCF EDAT- 2018/09/24 06:00 MHDA- 2019/10/29 06:00 CRDT- 2018/09/24 06:00 PHST- 2017/11/29 00:00 [received] PHST- 2018/09/12 00:00 [revised] PHST- 2018/09/18 00:00 [accepted] PHST- 2018/09/24 06:00 [pubmed] PHST- 2019/10/29 06:00 [medline] PHST- 2018/09/24 06:00 [entrez] AID - 10.1111/jnc.14596 [doi] PST - ppublish SO - J Neurochem. 2019 Jan;148(2):204-218. doi: 10.1111/jnc.14596. Epub 2018 Nov 12.