Regulation and Role of CREB in Cellular Genotoxic Response to Xenobiotics

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导致人类疾病，如癌症和神经变性。CREB似乎在各种组织中的细胞防御和存活中起关键作用;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然不完全清楚。CREB在Ser-133的磷酸化是主要的翻译后修饰，其增强CREB对受体偶联刺激的反应活性。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CREB Ser-133磷酸化的另一事件沿着似乎以刺激特异性方式参与CREB调节。本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HIPK 2（homeodomain interacting protein kinase 2），一种遗传毒性应激反应激酶，通过新的丝氨酸位点（Ser-271）而不是Ser-133的磷酸化激活CREB，导致CREB转录功能的激活。我们将测试我们的假设，HIPK 2是一个新的调节CREB转录因子通过磷酸化这个新的CREB网站，诱导细胞存活程序在遗传毒性和氧化应激条件。拟议的实验将集中在表征的分子机制，通过该CREB磷酸化的HIPK 2激活其转录功能，以及下游事件，包括靶基因的表达和细胞易感性的遗传毒性应激在体外和体内模型。这项研究的科学影响将是广泛和重要的，因为CREB调节细胞生长，分化，代谢和免疫反应等基本细胞事件。因此，成功完成这项提案所公布的新CREB调控将增强我们对与CREB活性密切相关的各种生理和疾病状况的理解。

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.