Regulation of MyoD Post-Transcriptional Modifications

MyoD 转录后修饰的调控

• 批准号: 6968392
• 负责人: Vittorio Sartorelli
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6968392
• 关键词: acetylation; amidohydrolases; cell differentiation; enzyme activity; gene expression; genetic transcription; microarray technology; muscle cells; nicotinamide adenine dinucleotide; phosphoproteins; posttranslational modifications; protein protein interaction; striated muscles

MyoD is a transcriptional activator required for muscle-specific gene expression. Expression of exogenous MyoD in numerous terminally differentiated cell lineages ( neurons, adipocytes, skin cells, chondrocytes adn others) redirect their fates towards the skeletal muscle phenotype. Furthermore, MyoD - and the related Myf-5 protein- is essential for the formation of skeletal muscles in the animal. In order to activate transcription, MyoD requires the assistance of other interacting partners such as the p300/CBP and PCAf coactivators. We have previously reported that p300 and PCAF are nodal coactivators of the muscle specific transcription factor MyoD. MyoD is acetylated by PCAF and this results in an increased DNA-binding and transcriptional activity. Acetylation and deacetylation are in a dynamic equilibrium and our studies have identified a role for the histone deacetylases (HDACs) in controlling muscle differentiation. To uncover the molecular mechanisms and the effectors that mediate the HDACs activity, we have used small molecules to inhibit the enzymatic activity of HDACs in skeletal muscle cells and performed microarray temporal profiling. Furthermore, prompted by the observation that the redox state fluctuates in skeletal muscle in response to modification of oxygen tension and glucose uptake, we have analyzed the role of the NAD+-dependent deacetylase Sir2 in controlling muscle gene expression.

MyoD是肌肉特异性基因表达所需的转录激活因子。外源性MyoD在许多终末分化细胞谱系（神经元、脂肪细胞、皮肤细胞、软骨细胞等）中的表达将其命运重定向至骨骼肌表型。此外，MyoD -和相关的Myf-5蛋白-对于动物骨骼肌的形成至关重要。为了激活转录，MyoD需要其他相互作用伙伴的帮助，例如p300/CBP和PCAf共激活因子。我们以前曾报道，p300和PCAF是肌肉特异性转录因子MyoD的节点共激活因子。MyoD被PCAF乙酰化，这导致DNA结合和转录活性增加。乙酰化和去乙酰化处于动态平衡，我们的研究已经确定了组蛋白去乙酰化酶（HDAC）在控制肌肉分化中的作用。为了揭示介导HDAC活性的分子机制和效应物，我们使用小分子来抑制骨骼肌细胞中HDAC的酶活性，并进行微阵列时间分析。 此外，提示的观察，在骨骼肌中的氧化还原状态波动，以响应修改的氧张力和葡萄糖的摄取，我们分析了NAD+依赖性脱乙酰酶Sir 2在控制肌肉基因表达的作用。