Regulation and Role of CREB in Cellular Genotoxic Response to Xenobiotics

CREB ​​在细胞对异生物质的基因毒性反应中的调节和作用

• 批准号: 8540440
• 负责人: YOSHIAKI TSUJI
• 金额: $ 26.46万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8540440
• 关键词: Address; Aging; Alzheimer' s Disease; Animal Model; Area; Binding; Binding Sites; Biology; Cancer Etiology; Cell Differentiation process; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cellular Stress Response; Chemicals; Coupled; Cyclic AMP Response Element; Cyclic AMP-Dependent Protein Kinases; Cyclic AMP-Responsive DNA-Binding Protein; DNA Damage; Defense Mechanisms; Development; Disease; EP300 gene; Event; Functional disorder; Gene Expression Regulation; Gene Targeting; Genetic Transcription; Genotoxic Stress; Histocompatibility Testing; Immune response; In Vitro; Lead; Long-Term Effects; Malignant Neoplasms; Metabolism; Molecular; Nerve Degeneration; Neuronal Plasticity; Neurons; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathway interactions; Phosphorylation; Phosphotransferases; Physiological; Play; Post-Translational Protein Processing; Post-Translational Regulation; Predisposition; Prevention; Problem Solving; Protein Kinase; Proteins; Recruitment Activity; Regulation; Regulatory Pathway; Research; Research Project Grants; Role; Serine; Signal Pathway; Signal Transduction; Site; Stimulus; Stress; Testing; Tissues; Toxic effect; Transactivation; Xenobiotics; biological adaptation to stress; cell growth; cell injury; cell type; genetic regulatory protein; homeodomain; human disease; improved; in vivo; in vivo Model; innovation; member; novel; programs; receptor coupling; research study; response; transcription factor

DESCRIPTION (provided by applicant): The CREB (cAMP-response element binding) transcription factor is a stimulus-induced phospho-protein that is involved in numerous cell signaling pathways. Dysfunction and deregulation of CREB and CREB- interacting proteins cause human diseases such as cancer and neurodegeneration. CREB appears to play a key role in cell defense and survival in various tissues; however, the mechanisms through which CREB is involved in cell survival and the reason why deregulation of CREB function causes these human diseases remain incompletely understood. CREB phosphorylation at Ser-133 is the major posttranslational modification that enhances CREB activity in response to receptor-coupled stimuli. However, the status of CREB Ser-133 phosphorylation was not always correlated with CREB transcription function, suggesting that another event along with CREB Ser-133 phosphorylation seems to be involved in CREB regulation in a stimulus-specific manner. This research project may provide evidence and a critical answer to these unsolved problems because we recently found that HIPK2 (homeodomain interacting protein kinase 2), a genotoxic stress responsive kinase, activates CREB via phosphorylation of a new serine site (Ser-271) but not Ser-133, resulting in activation of CREB transcription function. We will test our hypothesis that HIPK2 is a new regulator of the CREB transcription factor via phosphorylation of this new CREB site that induces a cell survival program in genotoxic and oxidative stress conditions. The proposed experiments will focus on characterization of molecular mechanism through which CREB phosphorylation by HIPK2 activates its transcription function as well as downstream events including expression of target genes and cellular susceptibility to genotoxic stress in in vitro and in vivo models. The scientific impact of this research will be broad and significant because CREB regulates essential cellular events such as cell growth, differentiation, metabolism, and immune response. Therefore the unveiled new CREB regulation from successful completion of this proposal will enhance our understanding in various physiological and disease conditions closely associated with the CREB activity.

描述(申请人提供)：CREB(cAMP反应元件结合)转录因子是一种刺激诱导的磷酸化蛋白，参与许多细胞信号通路。CREB和CREB相互作用蛋白的功能障碍和失控会导致癌症和神经变性等人类疾病。CREB似乎在多种组织的细胞防御和生存中发挥关键作用；然而，CREB参与细胞生存的机制以及CREB功能缺失导致这些人类疾病的原因仍不完全清楚。CREB在Ser-133处的磷酸化是主要的翻译后修饰，它增强了CREB的活性，以响应受体偶联刺激。然而，CREB Ser-133的磷酸化状态并不总是与CREB的转录功能相关，这表明与CREB Ser-133磷酸化一起的另一事件似乎以刺激特异性的方式参与了CREB的调控。这项研究可能为这些悬而未决的问题提供证据和关键的答案，因为我们最近发现，HIPK2(同源域相互作用蛋白激酶2)是一种遗传毒性应激反应蛋白，它通过激活一个新的丝氨酸位点(Ser-271)而不是Ser-133来激活CREB，导致CREB转录功能的激活。我们将通过这个新的CREB位点的磷酸化来验证我们的假设，即HIPK2是CREB转录因子的一个新的调节因子，它诱导细胞在遗传毒性和氧化应激条件下的生存程序。这些实验将集中于通过HIPK2磷酸化CREB激活其转录功能的分子机制及其下游事件的表征，包括在体外和体内模型中靶基因的表达和细胞对遗传毒性应激的敏感性。这项研究的科学影响将是广泛和重大的，因为CREB调节基本的细胞事件，如细胞生长、分化、新陈代谢和免疫反应。因此，这一提案的成功完成将加深我们对与CREB活性密切相关的各种生理和疾病情况的理解。