PARylation in genotoxic stress-induced NF-kB activation Supplement for Research on Sex/Gender Influences

 描述(申请人提供)：核因子-κB(核因子-κB)已被阐明为一种在多种细胞过程中的重要转录因子，而核因子-KappaB信号通路为药物干预提供了一个焦点。核转录因子κB对DNA损伤化学物质和电离辐射等遗传毒性威胁有反应。此外，NF-κB信号通路已成为细胞对遗传毒性应激反应的最重要的介导者之一，在过去的十年中，在理解κ损伤反应方面已经取得了相当大的进展，也就是说，各种遗传毒性应激后的“核-细胞质”的NF-κB信号通路仍然知之甚少，尤其是连接核DNA损伤和细胞质NF-DNA B激活的上游信号级联。我们最近的研究表明，Sam68(68 kDa有丝分裂期间的src相关底物)在dna损伤触发的NF-κB激活和调节中起关键作用 基因毒性应激诱导的聚(ADP-核糖基化)(PAR化)。本项目旨在阐明Sam68在DNA损伤启动的信号通路中的作用机制，并评估Sam68依赖的NF-κB信号在原代细胞培养、整个动物和人类癌细胞中的病理生理学意义。我们将在Aim 1中确定Sam68在遗传毒性应激启动的NF-κB信号通路中的作用，并在Aim 2中阐明Sam68如何调节DNA损伤后的PAR化的机制(S)。此外，在Aim 3中，我们将评估Sam68在遗传毒性应激诱导的小鼠原代细胞、整个动物和人类癌细胞中的NF-κB信号和激活中的作用。在这些研究的结论中，我们将阐明DNA损伤启动的导致NF-κB激活的上游信号级联反应的新的分子机制，从而促进我们对这一重要的“核质”NF-κB信号通路的基本理解。它还可能导致新的靶点，可能有助于合理开发治疗遗传毒性应激和核因子-κB相关疾病的药物。

 DESCRIPTION (provided by applicant): Nuclear factor kappa B (NF-κB) has been illustrated as an important transcription factor in a variety of cellular processes and the NF-κB signaling pathway has provided a focus for pharmacological intervention. NF-κB is responsive to genotoxic threats such as DNA damaging chemicals and ionizing irradiation. Moreover, the NF-κB signaling pathway has emerged as one of the most important mediators of the cellular responses to genotoxic stress, and considerable progress has been made during the past decade to understand DNA damage responses; that said, the ''nuclear-to-cytoplasmic'' NF-κB signaling pathways following various genotoxic stresses remain less defined, in particular the upstream signaling cascade that networks nuclear DNA damage and cytoplasmic NF-κB activation. Our recent study revealed that Sam68 (Src-associated substrate during mitosis of 68 kDa) is critical for the DNA damage-triggered NF-κB activation and regulates genotoxic stress-induced poly(ADP-ribosyl)ation (PARylation). This project aims to elucidate the mechanisms how Sam68 functions in the DNA damage-initiated signaling pathway, and to assess the pathophysiological significance of Sam68-dependent NF-κB signaling in primary cell cultures, whole animals, and human cancer cells. We will determine the role of Sam68 in genotoxic stress-initiated NF-κB signaling pathway in Aim 1 and elucidate the mechanism(s) how Sam68 regulates PARylation following DNA damage in Aim 2. Furthermore, we will assess the role of Sam68 in genotoxic stress-induced NF-κB signaling and activation in mouse primary cells, whole animals, and human cancer cells in Aim 3. At the conclusion of these studies, we will elucidate novel molecular mechanisms on DNA damage-initiated upstream signaling cascade that leads to NF-κB activation, thus advancing our fundamental understanding of this important "nuclear-to-cytoplasmic" NF-κB signaling pathway. It may also lead to novel targets that may aid rational drug development for the genotoxic stress- and NF-κB-associated diseases.