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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Functional evolution of the p53 regulatory network through its target response elements
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Functional evolution of the p53 regulatory network through its target response elements

机译：p53调控网络通过其目标响应元件的功能演变

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Transcriptional network evolution is central to the development of complex biological systems. Networks can evolve through variation of master regulators and/or by changes in regulation of genes within networks. To gain insight into meaningful evolutionary differences in large networks, it is essential to address the functional consequences of sequence differences in response elements (REs) targeted by transcription factors. Using a combination of custom bioinformatics and multispecies alignment of promoter regions, we investigated the functional evolution of REs in terms of responsiveness to the sequence-specific transcription factor p53, a tumor suppressor and master regulator of stress responses. We identified REs orthologous to known p53 targets in human and rodent cells or alternatively REs related to the established p53 consensus. The orthologous REs were assigned p53 transactivation capabilities based on rules determined from model systems, and a functional heat map was developed to visually summarize conservation of sequence and relative level of responsiveness to p53 for 47 REs in 14 species. Individual REs exhibited marked differences in transactivation potentials and widespread evolutionary turnover. Functional differences were often not predicted from consensus sequence evaluations. Of the established human p53 REs analyzed, 91 % had sequence conservation in at least one nonprimate species compared with 67.5% for functional conservation. Surprisingly, there was almost no conservation of functional REs for genes involved in DNA metabolism or repair between humans and rodents, suggesting important differences in p53 stress responses and cancer development.
机译：转录网络的进化对于复杂生物系统的发展至关重要。网络可以通过改变主调节子和/或通过改变网络内基因的调节来发展。为了深入了解大型网络中有意义的进化差异，必须解决转录因子靶向的反应元件（RE）中序列差异的功能后果。通过结合使用常规生物信息学和启动子区域的多物种比对，我们研究了REs对序列特异性转录因子p53，肿瘤抑制因子和应激反应调节因子的反应能力。我们确定了人类和啮齿动物细胞中与已知p53靶同源的RE，或者与已建立的p53共有蛋白相关的RE。基于从模型系统确定的规则，直系同源的稀土元素被赋予了p53反式激活能力，并且开发了功能热图以直观地总结了14种47种稀土元素对p53的序列保守性和相对水平。单个RE表现出明显的反式激活潜力差异和广泛的进化转换。通常不能从共有序列评估中预测功能差异。在已建立的已分析的人类p53 REs中，至少一种非灵长类物种具有91％的序列保守性，而功能保守性为67.5％。令人惊讶的是，人与啮齿动物之间几乎不存在涉及DNA代谢或修复的基因的功能性RE的保留，这表明p53应激反应和癌症的发展存在重要差异。

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