Regulation of NFkB & Beta-catenin by p13K/AKT/IKk path

NFkB的调节

• 批准号: 6888480
• 负责人: Nywana Sizemore
• 金额: $ 25.44万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6888480
• 关键词: I kappa B beta; apoptosis; biological signal transduction; cadherins; carcinogenesis; cell line; cell proliferation; cell transformation; colorectal neoplasms; enzyme activity; enzyme inhibitors; enzyme mechanism; gel mobility shift assay; gene expression; immunocytochemistry; microarray technology; nuclear factor kappa beta; phosphatidylinositol 3 kinase; phosphorylation; protein localization; protein protein interaction; protein structure function; transfection /expression vector; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): The transcription factors Nuclear factor kappa B (NFkappaB) and beta-catenin coordinate the expression of genes that control cell proliferation, survival, and transformation. We want to study the signal transduction pathways that lead to activation of these two transcription factors in colorectal carcinogenesis. Constitutive activation of the phosphatidylinositol 3' kinase (PI3K)/AKT pathway is frequently found in colorectal cancer and colorectal cancer cell lines. We have demonstrated a direct role of the PI3K/AKT cell survival pathway in controlling the activity of the I?a kinases (IKKs) towards the p65 NFkappaB transcription factor. Primary colorectal cancer tissue and many colorectal cancer cell lines show constitutive NFkappaB activity and maintenance of this activity seems to be necessary for colorectal cancer cell proliferation and resistance to apoptosis. We also have evidence that the IKKs regulate the activation of a-catenin, which has been shown to be a transcriptional regulator and an important contributing factor in colorectal carcinogenesis development by genetic data. We hypothesize that activation of AKT either by result of inactivation of its endogenous inhibitor, the tumor suppressor PTEN, or other oncogenic alterations result in the aberrant activation of the IKKs, which play important roles in inappropriate constitutive activation of NF?B and a-catenin in colorectal cancer. A major goal of this project is to determine how the IKKs control phosphorylation, activation, and integration of NF?B and a-catenin signaling in response to the PI3K/AKT and PTEN pathways. A second goal is to identify and study the regulation of NFkappaB dependent and a-catenin/Tcf/Lef-dependent genes important for controlling colorectal cancer cell proliferation, and survival as well as the impact of inhibiting the PI3K/AKT/IKK pathway in regulating these processes. A third goal is to examine the association between the PI3K/AKT/IKK pathway and the inappropriate activation of NF?B and a-catenin in colorectal cancer tissue.

描述（由申请人提供）：转录因子核因子 kappa B (NFkappaB) 和 β-连环蛋白协调控制细胞增殖、存活和转化的基因表达。 我们想要研究导致结直肠癌发生中这两种转录因子激活的信号转导途径。 磷脂酰肌醇 3' 激酶 (PI3K)/AKT 通路的组成型激活常见于结直肠癌和结直肠癌细胞系中。 我们已经证明 PI3K/AKT 细胞存活途径在控制 Iκa 激酶 (IKK) 对 p65 NFkappaB 转录因子的活性方面具有直接作用。 原发性结直肠癌组织和许多结直肠癌细胞系显示出组成型 NFkappaB 活性，并且这种活性的维持似乎对于结直肠癌细胞增殖和抗凋亡是必需的。 我们还有证据表明 IKK 调节α-连环蛋白的激活，遗传数据已表明α-连环蛋白是一种转录调节因子，也是结直肠癌发生发展的重要影响因素。 我们假设 AKT 的激活是由于其内源性抑制剂（肿瘤抑制因子 PTEN）失活或其他致癌改变导致 IKK 的异常激活，而 IKK 在结直肠癌中 NFκB 和 a-catenin 的不适当组成性激活中发挥着重要作用。 该项目的主要目标是确定 IKK 如何响应 PI3K/AKT 和 PTEN 途径控制 NFκB 和 a-catenin 信号传导的磷酸化、激活和整合。 第二个目标是确定和研究对控制结直肠癌细胞增殖和存活很重要的 NFkappaB 依赖性和 a-catenin/Tcf/Lef 依赖性基因的调节，以及抑制 PI3K/AKT/IKK 通路在调节这些过程中的影响。第三个目标是检查 PI3K/AKT/IKK 通路与结直肠癌组织中 NFκB 和 a-catenin 的不当激活之间的关联。