Dipeptidylpeptidase IV (DPP-IV) is a well-documented drug target for the treatment of type 2 diabetes. Hepatocyte nuclear factors (HNF)-1 alpha and HNF-1 beta, known as the causal genes of MODY3 and MODY5, respectively, have been reported to be involved in regulation of DPP-IV gene expression. But, it is not completely clear (i) that they play roles in regulation of DPP-IV gene expression, and (ii) whether DPP-IV gene activity is changed by mutant HNF-1 alpha and mutant HNF-1 alpha in MODY3 and MODY5. To explore these questions, we investigated transactivation effects of wild HNF-1 alpha and 13 mutant HNF-1 alpha, as well as wild HNF-1 beta and 2 mutant HNF-1 beta, on DPP-IV promoter luciferase gene in Caco-2 cells by means of a transient experiment. Both wild HNF-1 alpha and wild HNF-1 beta significantly transactivated DPP-IV promoter, but mutant HNF-1 alpha and mutant HNF-1 beta exhibited low transactivation activity. Moreover, to study whether mutant HNF-1 alpha and mutant HNF-1 beta change endogenous DPP-IV enzyme activity, we produced four stable cell lines from Caco-2 cells, in which wild HNF-1 alpha or wild HNF-1 beta, or else respective dominant-negative mutant HNF-1 alpha 539fsdelC or dominant-negative mutant HNF-I beta R177X, was stably expressed. We found that DPP-IV gene expression and enzyme activity were significantly increased in wild HNF-1 alpha cells and wild HNF-1 beta cells, whereas they decreased in HNF-1 alpha T539fsdelC cells and HNF-1 beta R177X cells, compared with DPP-IV gene expression and enzyme activity in Caco-2 cells. These results suggest that both wild HNF-1 alpha and wild HNF-lP have a stimulatory effect on DPP-IV gene expression, but that mutant HNF-1 alpha and mutant HNF-lP attenuate the stimulatory effect. (c) 2006 Elsevier Inc. All rights reserved.