Ubiquitination, Intestinal Homeostasis and Cancer

Abstract Adult intestinal tissues are maintained in a normal functional state despite rapidly proliferating and differentiating intestinal epithelial cell populations that replenish the epithelium layer every 6-7 days. Intestinal epithelial cells reside in close association with both adaptive and innate immune cells of the gut. A reciprocal and dynamic dialogue among these components maintains intestinal homeostasis and is mediated in part by paracrine cytokine and interleukin networks. Intestinal inflammation predisposes intestinal epithelial cells (IEC) to malignant transformation via incompletely understood mechanisms. We have generated a novel knock-in mouse line that spontaneously develops perturbed IEC differentiation, gut elongation, and have a high susceptibility to colon cancer. These mice provide us with a unique opportunity to discover the key inflammatory mediators that regulate intestinal homeostasis and drive IEC transformation. Using transcriptomic, proteomic, genetic epistasis and cellular approaches, our preliminary data implicate selected immune cytokines in these processes.