GKLF/Beta-Catenin Crosstalk in the Intestine

Transfer Proposal - Colorectal cancer is the second leading cause of cancer death in US. Most of colorectal cancers are caused by APC mutation or beta-catenin mutation. We found that KLF4 interacts with betacatenin and represses beta-catenin signaling and act as a tumor suppress. Our central hypothesis is that KLF4 inhibits beta-catenin signaling in the differentiated cells; conversely, beta-catenin inhibits KLF4 expression in proliferating cells, so KLF4lbeta-catenin crosstalk defines the proliferating and differentiating compartment in the intestine. Up-regulation of beta-catenin and down-regulation ofKLF4 together contributes to the initiation of colorectal cancers. We have three specific aims: 1) to delineate the mechanisms by which KLF4 inhibits betacatenin signaling; 2) to determine the mechanisms ofAPC-regulated KLF4-expression in colon cancer cells and APC-deleted intestine; and 3) to assess the functional effects ofKLF4lbetacatenin crosstalk.