Transcriptional profiling of calcineurin‐NFAT pathway in pancreatic growth

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Feeding protease inhibitor (PI) induces secretion of cholecystokinin (CCK) and leads to pancreatic growth. The phosphatase calcineurin (CN) is key to this process since its inhibition blocks this trophic response. To investigate early CN-dependent events, we pretreated mice with either a CN inhibitor FK506 (3mg/kg) or vehicle, fed them with PI for 2h and performed expression profiling using Affymetrix 430A GeneChips. Among 22,690 probe sets, FK506 significantly (>80% of vehicle, p<0.01) inhibited 58 probes, 38 of which were upregulated >3 fold by camostat. The probes represented 28 genes, which were organized into 3 groups, mainly, regulators of cell cycle/growth, cytoskeleton and metabolism. The CN-dependent genes comprised 25% of all genes upregulated by PI at 2h and showed similar pattern of highly upregulated expression for the first 1 and 2h of the 1-8h time course of PI feeding. Many effects of CN are mediated by Nuclear Factor of Activated T-cells (NFATs) and a study in our lab has shown that CCK activates CN-NFAT signaling. We computationally searched promoter regions of the CN-regulated gene set for NFAT binding sites and to date confirmed previously described NFAT-regulated gene (DSCR1) and predicted several new ones such as Gfi1 and Nurr1. Experimental validation by ChIP is underway.