PARylation in genotoxic stress-induced NF-kB activation

 描述（由申请人提供）：核因子κ B（NF-κB）已被证明是多种细胞过程中的重要转录因子，NF-κB信号通路为药物干预提供了焦点。NF-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，对DNA损伤反应的研究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”NF-κB信号通路仍然不太明确，特别是网络化核DNA损伤和细胞质NF-κB活化的上游信号级联。我们最近的研究表明，Sam 68（68 kDa有丝分裂过程中Src相关底物）对DNA损伤触发的NF-κB活化至关重要，并调节NF-κB的表达。 遗传毒性应激诱导的聚（ADP-核糖基）化（PAR化）。本项目旨在阐明Sam 68在DNA损伤启动的信号通路中的作用机制，并评估Sam 68依赖的NF-κB信号在原代细胞培养物、整个动物和人类癌细胞中的病理生理学意义。我们将确定Aim 1中Sam 68在遗传毒性应激启动的NF-κB信号通路中的作用，并阐明Aim 2中Sam 68如何调节DNA损伤后的PAR化的机制。此外，我们将在Aim 3中评估Sam 68在小鼠原代细胞、整个动物和人癌细胞中基因毒性应激诱导的NF-κB信号传导和活化中的作用。在这些研究的最后，我们将阐明新的分子机制，DNA损伤启动的上游信号级联，导致NF-κB激活，从而推进我们的基本理解这一重要的“核到胞质”NF-κB信号通路。它也可能导致新的目标，可能有助于合理的药物开发的遗传毒性应激和NF-κ B相关的疾病。

 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.