Studies in the Enders lab focus on the role of Cyclin dependent kinases (Cdks) in mammalian cell cycle control and tumorigenesis, with emphasis on gastrointestinal tumors.
Through conditional induction of a dominant negative mutant of Cdk2 and RNAi directed against cyclin A in human cells, we have obtained evidence that cyclin A/Cdk2 complexes drive activation of cyclin B/Cdk1 complexes. We are delineating the molecular events that are involved, including inactivation of the Cdk inhibitory kinase Wee1. These studies have provided insights for a revised model of mitotic entry in mammalian cells.
A second project addresses the mechanism of action of the tumor suppressor and Cdk inhibitor p16Ink4a. We have shown that expression of p16 in tissue culture results in a cell cycle block that evolves over several days into senescence. We are studying the tumor biology of p16 in the intestine, a major site of action. p16 is expressed in a subset of non-neoplastic and neoplastic colon cells with properties of stem cells. We are taking advantage of the mouse as a genetically tractable model system for studying p16 in gut epithelium. We have crossed mice carrying the Min (multiple intestinal neoplasia) mutation to Ink4a-knockout mice (defective in p16) and observed increased growth and vascularity of colon tumors, associated with higher levels of vascular endothelial growth factor (VEGF). We have generated new mouse transgenic models with enhance expression of VEGF in the intestine, to examine how it alters tumorigenesis. Thus, we are studying whether p16 acts within stem cells, mediates key effects on paracrine signaling, and/or imposes senescence in this physiologic setting of function.
p16-null colon tumor
We have recently initiated a project with David Weinberg studying Barrett’s esophagus. Barrett’s is an important pre-malignant metaplasia in which the normal squamous epithelium is replaced by an intestinal-like columnar epithelium. Disease progression is associated with DNA damage and p16 inactivation. We are prospectively collecting tissue from Barrett’s patients and analyzing markers of the DNA damage checkpoint response and associated cell cycle delays. We seek a better understanding the pathogenesis of the disease and markers of cancer risk of potential clinical utility.