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Peptones Stimulate Intestinal Cholecystokinin Gene Transcription via Cyclic Adenosine Monophosphate Response Element-Binding Factors

Institut National de la Santé et de la Recherche Médicale U45 (C.B., A.S., C.R., J.-A.C., M.C-B.), Hôpital Edouard Herriot, 69437 Lyon, France; Elève de l’Ecole Pratique des Hautes Etudes (A.S.); and Laboratory of Metabolism (C.V.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892

Address all correspondence and requests for reprints to: Dr. Martine Cordier-Bussat, INSERM U45, Hôpital Edouard Herriot, Pavillon Hbis, 69437 Lyon Cedex 03, France. E-mail: cordier{at}lyon151.inserm.fr

Cholecystokinin (CCK) is a potent intestinal hormone that regulates several digestive functions. Despite the physiological importance of CCK, the cellular and molecular mechanisms that govern its synthesis and secretion are not completely identified. Peptones, which are fair counterparts of the protein fraction in the intestinal lumen, are good stimulants of CCK secretion. We have previously shown that peptones activate CCK gene transcription in STC-1 enteroendocrine cells. The DNA element(s) necessary to induce the transcriptional stimulation was preliminary, localized in the first 800 bp of the CCK gene promoter. In the present study, we identify a DNA element [peptone-response element (PepRE)] essential to confer peptone-responsiveness to the CCK promoter, and we characterize the transcription factors implicated. Localization of the PepRE between -93 and -70 bp of the promoter was established using serial 5'-3'deletions. Systematic site-directed mutagenesis demonstrated that the core PepRE sequence, spanning from nucleotide -72 to -83, overlapped with the putative AP-1/CRE site. Mutations in the core sequence dramatically decreased peptone-responsiveness of CCK promoter fragments. The PepRE functioned as a low-affinity CRE consensus site, binding only transcription factors of the CREB family. Overexpression, in STC-1 cells, of a dominant-negative protein (A-CREB), that prevented the binding of CREB factors to DNA, completely abolished the peptone-induced transcriptional stimulation. Peptone treatment did not modify the nature and the abundance of proteins bound to the PepRE but led to increased phosphorylation of the CREB factors. In conclusion, the present study first demonstrates that CCK gene expression is under the control of protein-derived nutrients in the STC-1 enteroendocrine cell line.

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