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.
