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（由申请人提供）：该项目的目标是检查 NF-κB 的 p50 亚基在 DNA 烷基化损伤反应中的作用，作为改善恶性神经胶质瘤临床治疗的先决条件。恶性神经胶质瘤影响了 20,000 多个新病例。在美国，尽管采取了积极的治疗，但每年仍有约 1 年的患者存活。现在，TMZ 已成为治疗恶性胶质瘤的标准化疗药物，虽然它可以提高总体生存率，但许多患者的获益甚微。尽管 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存在。重要的是，下游通路代表了可以通过调节来提高治疗效果的靶标，我们工作的中心假设是 NF-κB，特别是 p50 信号传导，可以调节细胞毒性。我们的目标是检查 p50 反应的连续方面，以发现改善这种疾病治疗的新策略。在目标 1 中，我们将扩展对 p50 的研究。亚基本身及其翻译后 修饰（PTM），以检验磷酸化依赖性 p50 单泛素化对于 TMZ 的细胞毒性是必要的这一假设。通过无偏分析，我们已经鉴定出肿瘤抑制因子 Bard1 是介导 p50 单泛素化的 E3 连接酶。在目标 2 中，我们将分析重点转向 NF-κB 共有元件的 p50 一半（κB 位点）。 RNA 解旋酶 UAP56 作为 TMZ 细胞毒性所需的 κB 位点的新伴侣，我们将研究以下假设：UAP56 的启动子特异性苏酰化响应 TMZ 转录调节相互作用转录调节 NF-κB 反应以促进细胞毒性。最后，在目标 3 中，我们将根据初步观察结果，将我们的研究转化为检查临床恶性神经胶质瘤，即 p50 协同调节因子 Bcl3 对于恶性神经胶质瘤是必需的。 TMZ 诱导 p50 依赖性抗凋亡因子 具体来说，我们将检验 Bcl3 表达是恶性肿瘤临床生物标志物的假设。 至关重要的是，我们已经确定碳酸酐酶 II (CA2) 是一种独特的 Bcl3 依赖性因子，可以针对预计对 TMZ 反应不佳的肿瘤。这些互补的目标构建了 p50 如何与协同调节因子相互作用的总体图景，以启动子特异性的方式介导对 DNA 损伤的反应。此外，从更广泛的角度来看，考虑到这一点。 p50 介导对激活 ATR 和复制应激的任何试剂或过程的反应，当前项目的结果还将扩展我们对细胞如何对外源以及正常复制过程中诱导的复制应激做出反应的一般理解。