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

NFkB的调节

• 批准号: 6727708
• 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/6727708
• 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-catenin协调控制细胞增殖，存活和转化的基因的表达。 我们想研究导致结直肠癌中这两个转录因子激活的信号转导途径。 在结直肠癌和结直肠癌细胞系中经常发现磷脂酰肌醇3'激酶（PI3K）/AKT途径的组成型激活。 我们已经证明了PI3K/AKT细胞存活途径的直接作用在控制I？A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A AMASE（IKKS）对P65 NFKAPPAB转录因子的活性中发挥了作用。 原发性结直肠癌组织和许多结直肠癌细胞系显示了构成性NFKAPPAB活性，并且该活性的维持似乎对于结直肠癌细胞的增殖和对凋亡的抗性是必不可少的。 我们还有证据表明，IKKS调节了A-catenin的激活，A-catenin已被证明是转录调节剂，并且是通过遗传数据引起大肠癌发生发展的重要因素。 我们假设由于其内源性抑制剂的失活，肿瘤抑制剂PTEN或其他致癌改变会导致AKT的激活导致IKK的异常激活，而IKK的激活异常，在结直肠癌中NF？B和A-catenin的不适当组成型激活中起着重要作用。 该项目的一个主要目标是确定IKKS如何控制NF？B和A-Catenin信号的磷酸化，激活和整合，以响应PI3K/AKT和PTEN途径。 第二个目标是识别和研究NFKAPPAB依赖性和A-catenin/tcf/LEF依赖性基因对控制结直肠癌细胞的增殖以及抑制PI3K/AKT/IKK途径在调节这些过程中的影响以及抑制PI3K/AKT/IKK途径的影响。第三个目标是检查PI3K/AKT/IKK途径与结直肠癌组织中NF？B和A-catenin的不适当激活之间的关联。