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剂。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）中的表达将它们的命运转向骨骼肌表型。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。我们之前报道过 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，从而导致 DNA 结合和转录活性增加。乙酰化和脱乙酰化处于动态平衡，我们的研究已经确定了组蛋白脱乙酰酶 (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子，我们使用小分子抑制骨骼肌细胞中 HDAC 的酶活性，并进行了微阵列时间分析。 此外，根据骨骼肌中氧化还原状态随氧张力和葡萄糖摄取的变化而波动的观察结果，我们分析了 NAD+ 依赖性脱乙酰酶 Sir2 在控制肌肉基因表达中的作用。