REGULATION AND FUNCTION OF THE PUTATIVE TRANSCRIPTION FACTOR GADD153

假定转录因子 GADD153 的调节和功能

• 批准号: 2447738
• 负责人: N J HOLBROOK
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 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/2447738
• 关键词: arsenic; chemical kinetics; environmental toxicology; gene induction /repression; genetic promoter element; intermolecular interaction; physiologic stressor; protein structure function; stress proteins; tissue /cell culture; transcription factor

GADD153 is a highly conserved mammalian gene whose expression is increased in response to a variety of stresses including growth arrest and DNA damage. A member of the CCAAT/enhancer-binding protein (C/EBP) family of transcriptional activators, it can dimerize with other C/EBPs through a leucine zipper domain. However, in contrast to other C/EBPs, it lacks the ability to bind to CCAAT DNA sequences and has therefore been proposed to serve as a negative regulator of other members of this family (by virtue of its ability to heterodimerize with them and inhibit their binding to DNA). Members of the C/EBP family are thought to play important roles in adipocyte differentiation and liver specific gene expression. Studies in our laboratory suggest that C/EBPs are also likely to serve a more ubiquitous role in regulating gene expression during the cellular response to stress. Studies in this project have focused on (1) the regulation and function of GADD153 in response to diverse environmental stresses; (2) definition of critical regulatory elements in the GADD153 promoter which control its activity in response to stress, and (3) examination of interactions between GADD153 and other related transcription factors during various conditions of stress. The most important finding during the past year has been the demonstration that GADD153 interacts directly with C/EBP beta during the cellular response to treatment with arsenite, a metabolic stress. Based on these interactions, the kinetics of GADD153 and C/EBP beta induction following exposure to arsenite, and additional observations indicating that C/EBP beta can transactivate the GADD153 promoter through interaction at a C/EBP binding site, we have proposed a model whereby GADD153 acts through an autoregulatory feedback loop to attenuate its own expression through interference with C/EBP beta. In addition we have obtained preliminary evidence to suggest that other transcription factors including ATF3 and junD also contribute to regulate the transcriptional activity of the GADD153 promoter during stress. Current studies are aimed at further defining their role in regulating GADD153 expression.

GADD 153是一个高度保守的哺乳动物基因，其表达是 增加，以应对各种压力，包括生长停滞 和DNA损伤 CCAAT/增强子结合蛋白的一个成员 （C/EBP）家族的转录激活因子，它可以与其他转录因子二聚化。 C/EBP通过亮氨酸拉链结构域。然而，与其他 C/EBP，它缺乏与CCAAT DNA序列结合的能力， 因此被提议作为其他负调节器 该家族的成员（凭借其与 并抑制它们与DNA的结合）。 C/EBP家族的成员包括 被认为在脂肪细胞分化和肝脏中发挥重要作用 特异性基因表达 我们实验室的研究表明，C/EBP 也可能在调节基因表达方面起着更普遍的作用。 在细胞对应激的反应中表达。 本项目的研究 重点研究了（1）GADD 153的调节和功能， （2）不同的环境压力;（3）关键监管的定义 GADD 153启动子中的元件，其控制其响应 （3）检查GADD 153与其他 相关转录因子在各种应激条件下。 的 在过去的一年里，最重要的发现是， GADD 153在细胞凋亡过程中直接与C/EBP β相互作用， 对亚砷酸盐治疗的反应，一种代谢应激。 基于这些 GADD 153和C/EBP β诱导的动力学， 暴露于亚砷酸盐，以及其他观察结果表明，C/EBP β可以通过与GADD 153启动子的相互作用反式激活GADD 153启动子。 C/EBP结合位点，我们提出了GADD 153的作用模型， 通过自动调节反馈回路来减弱自身的表达 通过干扰C/EBP β。 此外，我们还获得了 初步证据表明，其他转录因子， ATF 3和junD也有助于调节转录活性。 GADD 153启动子在胁迫下的表达。 目前的研究旨在 进一步确定了它们在调节GADD 153表达中的作用。