Regulation of NFkB & Beta-catenin by pI3K/AKT/IKk path

描述(申请人提供)：转录因子核因子kappaB(NFkappaB)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。我们想要研究在结直肠癌发生过程中导致这两个转录因子激活的信号转导途径。磷脂酰肌醇3‘激酶(PI3K)/AKT通路的结构性激活在结直肠癌和结直肠癌细胞系中普遍存在。我们已经证明了PI3K/AKT细胞存活通路在控制I？A激酶(IKKS)对p65 NFkappaB转录因子的活性中起直接作用。原发结直肠癌组织和许多结直肠癌细胞系都显示出结构性的NFkappaB活性，维持这种活性似乎对结直肠癌细胞的增殖和抗凋亡是必要的。我们也有证据表明，IKKS调节α-连环蛋白的激活，基因数据表明，α-连环蛋白是一种转录调节因子，是结直肠癌发生发展的重要贡献因素。我们推测，AKT的激活可能是由于其内源性抑制物、抑癌基因PTEN失活或其他致癌基因的改变导致了IKK的异常激活，这在结直肠癌中核因子？B和α-连环蛋白的不适当结构性激活中发挥了重要作用。该项目的一个主要目标是确定IKKS如何控制PI3K/AKT和PTEN信号通路中核因子？B和α-连环蛋白信号的磷酸化、激活和整合。第二个目标是识别和研究NFkappaB依赖和a-catenin/Tcf/Lef依赖的基因的调控，这些基因对控制结直肠癌细胞的增殖和生存至关重要，以及抑制PI3K/AKT/IKK通路在调控这些过程中的影响。第三个目标是研究PI3K/AKT/IKK通路与结直肠癌组织中核因子？B和α-连环蛋白的不适当激活之间的关系。

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.