NF-kB1-p50 in the Response to DNA Alkylation Damage

NF-kB1-p50 对 DNA 烷基化损伤的反应

• 批准号: 9102988
• 负责人: Bakhtiar Yamini
• 金额: $ 33.77万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9102988
• 关键词: Address; Adult; Affect; Alkylating Agents; Apoptotic; Attenuated; Binding; Biological Markers; Carbonic Anhydrase II; Cell Death; Cells; Clinical; Clinical Management; Complex; Consensus; DNA Alkylation; DNA Damage; DNA Double Strand Break; Data Set; Databases; Diagnosis; Disease; Effectiveness; Elements; Funding; Gene Expression; Genes; Glioma; Goals; Health; Lesion; Malignant Glioma; Malignant Neoplasms; Mediating; Messenger RNA; Mono-S; Nuclear; Nucleotides; Pathway interactions; Patient-Focused Outcomes; Patients; Phosphorylation; Play; Post-Translational Protein Processing; Process; Proteins; RNA Helicase; Reporting; Resistance; Role; Sampling; Series; Signal Pathway; Signal Transduction; Site; Stratification; Stress; TNFRSF5 gene; Testing; Therapeutic; Therapeutic Effect; Translating; Tumor Suppressor Proteins; Ubiquitination; Work; aggressive therapy; base; clinical biomarkers; cytotoxic; cytotoxicity; enhancing factor; experience; improved; inhibitor/antagonist; killings; novel; novel marker; novel strategies; prognostic; promoter; protein expression; repaired; research study; response; temozolomide; transcription factor; tumor; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): The goal of this project is to examine the role of the p50 subunit of NF-κB in the response to DNA alkylation damage as a prerequisite to improving the clinical management of malignant glioma. Malignant glioma affects over 20,000 new patients in the US each year and despite aggressive therapy, patient survival remains about 1 year. The alkylating agent, temozolomide (TMZ), is now the standard chemotherapeutic used in the treatment of malignant glioma, and while it improves overall survival, many patients experience minimal benefit. Although the upstream lesions and repair mechanisms that modulate cytotoxicity by TMZ are well elucidated, the downstream signaling that ultimately mediates cell death remains less well studied. Importantly, downstream pathways represent targets that can be modulated to improve the therapeutic effect. The central hypothesis of our work is that NF-κB, and p50 signaling in particular, regulates the cytotoxic response to TMZ and that therapeutic modulation of this pathway can improve the effectiveness of TMZ. Our aims examine sequential aspects of the p50 response to uncover novel strategies to improve the treatment of this disease. In Aim 1, we will extend our studies of the p50 subunit itself, and its post-translational modification (PTM), to examine the hypothesis that phosphorylation-dependent p50 mono-ubiquitination is necessary for cytotoxicity by TMZ. Using unbiased analysis, we have identified the tumor suppressor, Bard1, as being the E3-ligase that mediates p50 mono-ubiquitination. In Aim 2, we shift our analysis to focus on the p50 half of the NF-κB consensus element (κB-site). Specifically, we have identified the RNA helicase, UAP56, as a novel interacting partner of the κB-site that is required for cytotoxicity by TMZ. We will examine the hypothesis that promoter specific sumoylation of UAP56 in response to TMZ transcriptionally regulates the NF-κB response to promote cytotoxicity. Finally, in Aim 3, we will translate our studies to examine clinical malignant gliomas based on the preliminary observation that the p50 co-regulator, Bcl3, is necessary for induction of p50-dependent anti- apoptotic factors in response to TMZ. Specifically, we will test the hypothesis that Bcl3 expression is a clinical biomarker in malignant glioma and that targeting Bcl3-dependent factors enhances the overall anti-glioma effect. Crucially, we have identified carbonic anhydrase II (CA2) as a unique Bcl3-dependent factor that can be targeted to sensitize tumors that are predicted to respond poorly to TMZ. These complimentary aims build a general picture of how p50 interacts with co-regulators, in a promoter-specific manner to mediate the response to DNA damage. In addition, from a broader perspective, given that p50 mediates the response to any agent or process that activates ATR and replication stress, the results of the current project will also expand our general understanding of how cells respond to replication stress induced not only exogenously but also during normal replication.

 描述（由适用提供）：该项目的目的是检查NF-κB的P50亚基在对DNA酗酒损害的响应中的作用，这是改善恶性神经胶质瘤的临床管理的先决条件。恶性神经胶质瘤每年在美国影响20,000多名新患者，并希望进行侵略性疗法，患者的生存率仍然约为1年。酗酒剂Temozolamide（TMZ）现在是用于治疗恶性神经胶质瘤的标准化疗，尽管它提高了整体生存率，但许多患者的益处最少。尽管通过TMZ调节细胞毒性的上游病变和修复机制已得到很好的阐明，但最终介导细胞死亡的下游信号传导仍然不那么良好。重要的是，下游途径表示可以调节以改善治疗效果的目标。我们工作的中心假设是NF-κB和P50信号传导调节对TMZ的细胞毒性反应，并且该途径的治疗调节可以提高TMZ的有效性。我们的目的是研究P50反应的顺序方面，以发现改善该疾病治疗的新型策略。在AIM 1中，我们将扩展对P50亚基本身及其翻译后的研究 修改（PTM），以检验以下假设：磷酸化依赖性p50单泛素化对于TMZ的细胞毒性是必不可少的。使用公正的分析，我们将肿瘤抑制剂Bard1确定为介导p50单泛素化的E3型酶酶。在AIM 2中，我们将分析转移到NF-κB共有元件（κB位置）的P50一半。具体而言，我们已经将RNA解旋酶UAP56确定为TMZ细胞毒性所需的新型相互作用伴侣。我们将研究以下假设：启动子对TMZ的转录响应UAP56的特异性Sumoylation会调节NF-κB反应以促进细胞毒性。最后，在AIM 3中，我们将基于初步观察结果来转换研究以检查临床恶性神经胶质瘤，即P50共同调节剂BCl3对于诱导P50依赖性抗凋亡因子是响应TMZ所必需的。具体而言，我们将检验以下假设：Bcl3表达是恶性肿瘤的临床生物标志物 神经胶质瘤和靶向Bcl3依赖性因子增强了总体抗脱糖瘤作用。至关重要的是，我们已经将碳酸酐酶II（Ca2）确定为独特的Bcl3依赖性因子，可以针对敏感肿瘤，预计对TMZ的反应不佳。这些免费的目的以特定于启动子特异性的方式构建了P50如何与共同调节器相互作用的一般图片，以介导对DNA损伤的响应。此外，从更广泛的角度来看，鉴于P50介导了激活ATR和复制应力的任何药物或过程的反应，因此当前项目的结果还将扩展我们对细胞对细胞对复制应力的反应不仅造成的复制应力的一般理解，不仅是外源引起的，而且在正常复制过程中。