Regulation of inducible cAMP early repressor expression by gastrin and cholecystokinin in the pancreatic cell line AR42J.
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 G(q)/G(11) protein-coupled receptors.
Thommesen
L
L
Department of Physiology and Biomedical Engineering, Norwegian University of Science and Technology, N-7489 Trondheim, Norway.
Nørsett
K
K
Sandvik
A K
AK
Hofsli
E
E
Laegreid
A
A
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002460:Cell Line; D002766:Cholecystokinin / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000235:genetics*; D051786:Cyclic AMP Response Element Modulator; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005755:Gastrins / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000235:genetics; D020932:Nerve Growth Factor / Q000494:pharmacology; D016716:PC12 Cells; D010179:Pancreas; D010671:Phenylurea Compounds / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015533:Transcriptional Activation
D001570:Benzodiazepinones; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D005755:Gastrins; D010671:Phenylurea Compounds; D012097:Repressor Proteins; D051786:Cyclic AMP Response Element Modulator; C090649:L 740093; D005576:Colforsin; D004815:Epidermal Growth Factor; D002766:Cholecystokinin; D020932:Nerve Growth Factor; D000242:Cyclic AMP; D013755:Tetradecanoylphorbol Acetate