A role for p53/MyoD redundancy in myogenesis?

p53/MyoD 冗余在肌生成中的作用？

• 批准号: 7009150
• 负责人: SANDRA B SHARP
• 金额: $ 20.31万
• 依托单位: CALIFORNIA STATE UNIVERSITY LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-05 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7009150
• 关键词: gene expression; gene mutation; gene redundancy; genetically modified animals; laboratory mouse; microarray technology; molecular biology; myogenesis; p53 gene /protein; protein structure function; regulatory gene; striated muscles; transcription factor

DESCRIPTION (provided by applicant): This proposal is part of a larger goal to understand myogenesis of skeletal muscle at the molecular level. Developmental processes are controlled by both tissue specific and generally expressed regulatory factors. For example, cell culture experiments have shown that both primary and immortal mouse myoblasts that express the muscle specific transcription factor MyoD but that lack tumor suppressor regulatory protein p53 activity are of limited myogenic capacity. Assays done thus far with whole mouse experiments, however, have revealed no apparent role for p53 in myogenesis. The cell culture and in vivo results together suggest a model in which p53 and MyoD play partially redundant roles. Indeed, examples of p53/MyoD redundancy are known and at least one muscle-specific gene, muscle creatine kinase, is thought to be coregulated by MyoD and p53. Preliminary results have presented additional genes that are candidates for regulation by MyoD and/or p53. Development in vivo is likely to invoke compensatory mechanisms that are unavailable to cells in culture. We hypothesize, therefore, that while failure to express either p53 or MyoD may be of less apparent consequence in the whole animal than it is in cell culture, failure to express both MyoD and p53 might result in abnormal muscle development. Analysis of p53/MyoD double knockout mice will be used to determine whether successful myogenesis requires that eitherp53 or MyoD be present. Microarray expression analysis will be used to catalog candidate genes for redundant or combinatoric regulation. The identification of activities that are regulated by either MyoD or p53 will generate testable hypotheses about how these activities affect myogenesis and about why cancer frequently results in loss of the differentiated phenotype. To the extent that MyoD and p53 are redundant, it will be important to consider relevant domains of MyoD for applications in cancer treatment.

描述（由申请人提供）：该建议是了解分子水平上骨骼肌的肌发生的更大目标的一部分。发育过程受组织特异性和通常表达的调节因素控制。例如，细胞培养实验表明，表达肌肉特异性转录因子myod但缺乏肿瘤抑制剂调节蛋白p53活性的原代和不朽的小鼠成肌细胞具有有限的肌源能力。然而，迄今为止，通过整个小鼠实验进行的测定表明，p53在肌发生中没有明显的作用。细胞培养和体内结果共同提出了一个模型，其中p53和Myod扮演了部分冗余角色。实际上，p53/myod冗余的例子是已知的，至少一个肌肉特异性基因肌肉肌酸激酶被Myod和p53构造了。初步结果提出了其他基因，这些基因是Myod和/或p53进行调节的候选者。体内发育可能会引起培养细胞无法获得的补偿机制。因此，我们假设，尽管未能表达p53或myod的表达可能比细胞培养中的明显影响较小，但未能同时表达MYOD和p53可能会导致异常的肌肉发育。对p53/myod双基因敲除小鼠的分析将用于确定成功的肌发生是否需要P53或MYOD存在。微阵列表达分析将用于分类候选基因，以进行冗余或组合调节。鉴定由MYOD或p53调节的活动将产生有关这些活动如何影响肌发生以及为什么癌症经常导致分化表型丧失的可检验假设。在一定程度上，Myod和p53是多余的，重要的是要考虑MYOD的相关领域用于癌症治疗中的应用。