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

描述（由申请方提供）：转录因子核因子κ B（NF κ B）和β-连环蛋白协调控制细胞增殖、存活和转化的基因的表达。 我们希望研究导致这两种转录因子在结直肠癌发生中激活的信号转导途径。 磷脂酰肌醇3'激酶（PI 3 K）/AKT通路的组成性激活经常在结直肠癌和结直肠癌细胞系中发现。 我们已经证明了PI 3 K/AKT细胞存活途径在控制I？a激酶（IKK）对p65 NF κ B转录因子的作用。 原发性结直肠癌组织和许多结直肠癌细胞系显示组成性NF κ B活性，并且维持这种活性似乎是结直肠癌细胞增殖和抗凋亡所必需的。 我们也有证据表明IKK调节α-连环蛋白的激活，α-连环蛋白已被证明是一种转录调节因子，并且通过遗传数据是结直肠癌发生发展的重要促成因素。 我们假设激活AKT的内源性抑制剂，抑癌基因PTEN的失活，或其他致癌改变的结果，在异常激活的IKKs，发挥重要作用，在不适当的组成性激活NF？结直肠癌中的B和α-连环蛋白。 这个项目的一个主要目标是确定IKK如何控制NF的磷酸化、激活和整合？B和α-连环蛋白信号传导对PI 3 K/AKT和PTEN途径的响应。 第二个目标是鉴定和研究对控制结肠直肠癌细胞增殖和存活重要的NF κ B依赖性和α-连环蛋白/Tcf/Lef依赖性基因的调节，以及抑制PI 3 K/AKT/IKK通路在调节这些过程中的影响。第三个目标是研究PI 3 K/AKT/IKK通路与NF？结直肠癌组织中B和α-连环蛋白的表达。

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.