Background: To define the molecular mechanisms underlying the intestinal adaptive response after partial small bowel resection, we previously identified a cohort of genes regulated in the remnant adaptive ileum. One is PC4/TIS7, an immediate early gene preferentially up-regulated during the first 48 hours after resection. To further specify the mechanisms that regulate gut adaptation, we sought to identify upstream regulators of PC4/TIS7 expression. Methods: PC4/TIS7 expression in adaptive versus transection control mouse gut was examined at 48 hours after 50% intestinal resection, and its cellular localization was determined by immunohistochemistry. The effects of intestinotrophic peptides and growth factors on PC4/TIS7 expression were examined in vitro in the crypt epithelial cell line IEC 18 and in vivo in the mouse. Results: PC4/TIS7 was expressed in the cytoplasm of IEC 18 cells and in adaptive mouse ileal crypt and villus enterocytes. Epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) increased PC4/TIS7 mRNA levels in postconfluent, quiescent IEC 18 cells, but insulin-like growth factor 1 (IGF-1) and nerve growth factor (NGF) had no effect. A stable derivative of glucagon-like peptide 2 (GLP-2), r(gly2)GLP-2, was most potent in increasing PC4/TIS7 expression; however, stimulation of proliferation and differentiation were not observed. To determine the effect of GLP-2 on PC4/TIS7 expression in vivo, r(gly2)GLP-2 was administered intraperitoneally to mice. PC4/TIS7 mRNA expression was increased in small bowel in response to GLP-2 compared with vehicle control. Conclusions: These results suggest that PC4/TIS7 plays a role in intracellular signaling in the intestinal epithelium during the adaptive response, possibly as a common downstream effector for several intestinotrophic growth factors.