Regulation of Inducible cAMP Early Repressor Expression by Gastrin and Cholecystokinin in the Pancreatic Cell Line AR42J

• Published in: The Journal of biological chemistry 2000-02, Vol.275 (6), p.4244-4250
• Main Authors: Thommesen, Liv, Nørsett, Kristin, Sandvik, Arne K., Hofsli, Eva, Lægreid, Astrid
• Format: Article
• Language: English
• Subjects: Animals; Benzodiazepinones - pharmacology; Cell Line; Cholecystokinin - pharmacology; Colforsin - pharmacology; CREM gene; Cyclic AMP - genetics; Cyclic AMP Response Element Modulator; Cyclic AMP Response Element-Binding Protein - metabolism; DNA-Binding Proteins - genetics; Epidermal Growth Factor - pharmacology; forskolin; gastrin; Gastrins - pharmacology; Gene Expression Regulation - genetics; ICER gene; Nerve Growth Factor - pharmacology; Pancreas; PC12 Cells; Phenylurea Compounds - pharmacology; Phosphorylation; Rats; Repressor Proteins - genetics; Tetradecanoylphorbol Acetate - pharmacology; Transcriptional Activation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.275.6.4244

The CREM gene encodes both activators and repressors of cAMP-induced transcription. Inducible cAMP early repressor (ICER) isoforms are generated upon activation of an alternative, intronic promoter within the CREM gene. ICER is proposed to down-regulate both its own expression and the expression of other genes that contain cAMP-responsive elements such as a number of growth factors. Thus, ICER has been postulated to play a role in proliferation and differentiation. Here we show that ICER gene expression is induced by gastrin, cholecystokinin (CCK), and epidermal growth factor in AR42J cells. The time course of gastrin- and CCK-mediated ICER induction is rapid and transient, similar to forskolin- and phorbol 12-myristate 13-acetate-induced ICER expression. The specific CCK-B receptor antagonist L740,093 blocks the gastrin but not the CCK response, indicating that both the CCK-B and the CCK-A receptor can mediate ICER gene activation. Noteworthy, CREB is constitutively phosphorylated at Ser-133 in AR42J cells, and ICER induction proceeds in the absence of increased CREB Ser(P)-133. Gastrin-mediated ICER induction was not reduced in the presence of the protein kinase A inhibitor H-89, indicating a protein kinase A-independent mechanism. This is the first report on ICER inducibility via Gq/G11protein-coupled receptors.