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首页> 外文期刊>Molecular and Cellular Biology >Phosphorylation and Alternative Pre-mRNA Splicing Converge To Regulate Myocyte Enhancer Factor 2C Activity
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Phosphorylation and Alternative Pre-mRNA Splicing Converge To Regulate Myocyte Enhancer Factor 2C Activity

机译：磷酸化和替代性的前mRNA拼接聚合，以调节心肌细胞增强因子2C的活性。

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Myocyte enhancer factor 2 (MEF2) transcription factors play pivotal roles in cardiac, muscle, and neuron gene expression. All products of MEF2 genes have a common amino-terminal DNA binding and dimerization domain, but the four vertebrate MEF2 gene transcripts are alternatively spliced among coding exons to produce splicing isoforms. In MEF2C alone, alternative splice acceptors in the last exon give forms that include or exclude a short domain that we designate γ. We show that MEF2C is expressed exclusively as γ? isoforms in heart tissue and predominantly as γ? in other adult tissues and in differentiating myocytes. MEF2C γ? isoforms are much more robust than γ+ forms in activating MEF2-responsive reporters in transfected fibroblasts despite indistinguishable expression levels, and they better synergize with MyoD in promoting myogenic conversion. One-hybrid transcription assays using Gal4-MEF2C fusions give similar distinctions between γ? and γ+ isoforms in all cell types tested, including myocytes. Cis effects of γ on MEF2C DNA binding, dimerization, protein stability, or response to CaM or p38 mitogen-activated protein kinase signaling are not apparent, and the isolated γ domain represses transcription when fused to Gal4. One phosphoserine residue is present within the γ domain according to tandem mass spectrometry, and mutation of this residue abolishes γ-mediated transrepression. A similar activity is present in the constitutive γ domain and serine phosphoacceptor of MEF2A. Our findings indicate that γ functions autonomously as a phosphoserine-dependent transrepressor to downregulate transactivation function of MEF2 factors and that alternative splicing and serine phosphorylation converge to provide complex combinatorial control of MEF2C activity.
机译：心肌细胞增强因子2（MEF2）转录因子在心脏，肌肉和神经元基因表达中起关键作用。 MEF2 基因的所有产物均具有共同的氨基末端DNA结合和二聚结构域，但四个脊椎动物 MEF2 基因转录物可在编码外显子之间交替剪接以产生剪接同工型。仅在 MEF2C 中，最后一个外显子的替代剪接受体给出的形式包括或不包括我们指定的γ短域。我们证明 MEF2C 仅表示为γ？心脏组织中的同工型，主要为γ？在其他成年组织和分化中的肌细胞中。 MEF2Cγ？尽管表达水平无法区分，但同种型在激活转染的成纤维细胞中的MEF2反应性报告基因方面比γ+形式强大得多，并且它们在促进成肌转化方面与MyoD具有更好的协同作用。使用Gal4-MEF2C融合的单杂交转录测定法在γ？和所有测试细胞类型（包括肌细胞）中的γ+亚型。 γ对MEF2C DNA结合，二聚化，蛋白质稳定性或对CaM或p38丝裂原活化的蛋白激酶信号传导的应答的 Cis 作用尚不明显，并且与Gal4融合时，分离的γ结构域抑制转录。根据串联质谱法，在γ域中存在一个磷酸丝氨酸残基，并且该残基的突变消除了γ介导的反式抑制。在MEF2A的组成型γ域和丝氨酸磷酸受体中存在相似的活性。我们的发现表明，γ自主地发挥磷酸丝氨酸依赖性反式抑制子的功能，以下调MEF2因子的反式激活功能，并且选择性剪接和丝氨酸磷酸化融合以提供对MEF2C活性的复杂组合控制。

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