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Identification of the intermediate filament protein synemin/SYNM as a target of myocardin family coactivators.

Swärd, Karl; Krawczyk, Katarzyna K; Morén, Björn; Zhu, Baoyi; Matic, Ljubica; Holmberg, Johan; Hedin, Ulf; Uvelius, Bengt; Stenkula, Karin; Rippe, Catarina.
Artigo em Inglês | MEDLINE | ID: mdl-31461342
Myocardin (MYOCD) is a critical regulator of smooth muscle cell (SMC) differentiation, but its transcriptional targets remain to be exhaustively characterized, especially at the protein level. Here we used a bioinformatics approach to identify novel potential MYOCD targets, and we confirm several at the protein level, including SORBS1, SLMAP, SYNM, and MCAM. We focused on SYNM, which encodes the intermediate filament protein synemin. SYNM rivalled smooth muscle myosin (MYH11) for SMC specificity, and was controlled at the mRNA and protein levels by all myocardin-related transcription factors (MRTFs: MYOCD, MRTF-A/MKL1, and MRTF-B/MKL2). MRTF activity is regulated by the ratio of filamentous to globular actin, and SYNM was accordingly reduced by interventions that depolymerize actin, such as Latrunculin treatment and overexpression of constitutively active cofilin. Many MRTF target genes depend on SRF, but SYNM lacked SRF-binding motifs in its proximal promoter which was not directly regulated by MYOCD. Further, SYNM resisted SRF-silencing, and yet the time-course of induction closely paralleled that of the SRF-dependent target gene ACTA2. SYNM was repressed by the Ternary Complex Factor (TCF) FLI1, and was increased in mouse embryonic fibroblasts lacking three classical TCFs (ELK1, ELK3, and ELK4). Imaging showed co-localization of SYNM with the intermediate filament proteins desmin and vimentin, and MRTF-A/MKL1 increased SYNM-containing intermediate filaments in SMCs. These studies identify SYNM as a novel SRF-independent target of myocardin that is abundantly expressed in all SMCs.
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