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: 8185590
• 负责人: YOSHIAKI TSUJI
• 金额: $ 27.49万
• 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/8185590
• 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. PUBLIC HEALTH RELEVANCE: Genotoxic and oxidative stress induced by environmental and manmade chemicals are associated with human disease including cancer and neurodegeneration (such as Alzheimer and Parkinson's diseases), and aging; therefore, research to determine cellular defense mechanisms against the harmful stress is important for our understanding of the pathogenesis, prevention, and/or delay of these diseases. CREB is an essential transcription factor that plays critical roles in cell metabolism, differentiation, survival, and proliferation in various cell types. Indeed, accumulating evidence indicates that dysfunction and deregulation of CREB cause cancer and neuronal cell damage. CREB is involved in cell survival in genotoxic stress conditions; however, in contrast to intensive characterization of CREB in external stimuli that exert long-term effects such as cell differentiation and proliferation, molecular mechanisms behind CREB regulation in detrimental genotoxic and oxidative stress conditions remain largely unknown. This proposal will characterize a novel CREB regulatory pathway and mechanism we recently found, which are different from of a previously known CREB pathway. We anticipate that successful completion of proposed experiments will improve our understanding of how cells elicit CREB-regulated cell survival program against these stress and disease conditions. The impact of this research will be broad and significant in many research areas because the CREB transcription factor regulates numerous cellular functions in various types of tissues. Innovation of this research will include demonstration of a novel CREB signaling pathway and downstream target genes involved in stress response in cellular levels and an animal model.

描述（由申请人提供）：CREB（cAMP 反应元件结合）转录因子是一种刺激诱导的磷酸蛋白，参与多种细胞信号传导途径。 CREB ​​和 CREB ​​相互作用蛋白的功能障碍和失调会导致癌症和神经退行性疾病等人类疾病。 CREB ​​似乎在多种组织的细胞防御和存活中发挥着关键作用；然而，CREB ​​参与细胞存活的机制以及 CREB ​​功能失调导致这些人类疾病的原因仍不完全清楚。 CREB ​​Ser-133 磷酸化是主要的翻译后修饰，可增强 CREB ​​响应受体偶联刺激的活性。然而，CREB ​​Ser-133 磷酸化的状态并不总是与 CREB ​​转录功能相关，这表明与 CREB ​​Ser-133 磷酸化一起的另一个事件似乎以刺激特异性方式参与 CREB ​​调节。该研究项目可能为这些未解决的问题提供证据和关键答案，因为我们最近发现 HIPK2（同源域相互作用蛋白激酶 2）是一种基因毒性应激反应激酶，可通过新丝氨酸位点 (Ser-271) 的磷酸化激活 CREB，但不能Ser-133，导致 CREB ​​转录功能激活。我们将检验我们的假设，即 HIPK2 是 CREB ​​转录因子的新调节因子，通过磷酸化这个新的 CREB ​​位点，在基因毒性和氧化应激条件下诱导细胞生存程序。拟议的实验将重点关注 HIPK2 磷酸化 CREB ​​激活其转录功能的分子机制以及下游事件，包括体外和体内模型中靶基因的表达和细胞对基因毒性应激的敏感性。这项研究的科学影响将是广泛而重要的，因为 CREB ​​调节细胞生长、分化、代谢和免疫反应等重要的细胞事件。因此，该提案的成功完成所揭示的新的 CREB ​​监管将增强我们对与 CREB ​​活动密切相关的各种生理和疾病条件的理解。 公共健康相关性：环境和人造化学物质引起的基因毒性和氧化应激与人类疾病有关，包括癌症和神经退行性疾病（如阿尔茨海默病和帕金森病）以及衰老；因此，研究确定针对有害应激的细胞防御机制对于我们了解这些疾病的发病机制、预防和/或延迟非常重要。 CREB ​​是一种重要的转录因子，在各种细胞类型的细胞代谢、分化、存活和增殖中发挥着关键作用。事实上，越来越多的证据表明 CREB ​​的功能障碍和失调会导致癌症和神经元细胞损伤。 CREB ​​参与基因毒性应激条件下的细胞存活；然而，与CREB在细胞分化和增殖等长期影响的外部刺激中的强烈表征相反，有害基因毒性和氧化应激条件下CREB调节背后的分子机制仍然很大程度上未知。该提案将描述我们最近发现的一种新的 CREB ​​调控途径和机制，其与之前已知的 CREB ​​途径不同。我们预计，成功完成拟议的实验将提高我们对细胞如何针对这些压力和疾病条件引发 CREB ​​调节的细胞生存程序的理解。这项研究的影响将在许多研究领域产生广泛而重大的影响，因为 CREB ​​转录因子调节各种类型组织中的众多细胞功能。这项研究的创新将包括展示一种新的 CREB ​​信号通路以及参与细胞水平和动物模型应激反应的下游靶基因。