ICAT is a novel PTF1A interactor that regulates pancreatic acinar differentiation and displays altered expression in tumors

The Pancreas Transcription Factor 1 (PTF1) complex is a master regulator of differentiation of acinar cells, responsible for the production of digestive enzymes. In the adult pancreas, PTF1 contains two pancreas-restricted transcription factors: Ptf1a and Rbpjl. PTF1 recruits P/CAF which acetylates Ptf1a and enhances its transcriptional activity. Using a yeast two hybrid screening, we identified ICAT (Inhibitor of ß-Catenin and Tcf4) as a novel Ptf1a interactor. ICAT regulates the Wnt pathway and cell proliferation. We validated and mapped the ICAT-Ptf1a interaction in vitro and in vivo. We demonstrated that - upon its overexpression in acinar tumor cells - ICAT negatively regulates PTF1 activity in vitro and in vivo. This effect was independent of β-catenin and was mediated by direct binding to Ptf1a and displacement of P/CAF. ICAT also modulated the expression of Pdx1 and Sox9 in acinar tumor cells. ICAT overexpression reduced the interaction of Ptf1a with Rbpjl and P/CAF and impaired Ptf1a acetylation by P/CAF. ICAT did not affect the subcellular localization of Ptf1a. In human pancreas, ICAT displayed a cell-type specific distribution: in acinar and endocrine cells it was nuclear; in ductal cells, it was cytoplasmic. In ductal adenocarcinomas, ICAT displayed mainly a nuclear or mixed distribution and the former was an independent marker of survival. ICAT regulates acinar differentiation and it does so through a novel, Wnt pathway-independent, mechanism that ...
Source: BJ Cell - Category: Biochemistry Authors: Tags: BJ Disease Source Type: research