Signaling mechanisms regulating bombesin-mediated AP-1 gene induction in the human gastric cancer SIIA |
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Authors: | Kim H J Evers B M Litvak D A Hellmich M R Townsend C M |
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Institution: | Department of Surgery, The University of Chicago Medical Center, Illinois 60637, USA. |
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Abstract: | The hormone bombesin(BBS) and its mammalian equivalent gastrin-releasing peptide (GRP) actthrough specific GRP receptors (GRP-R) to affect multiple cellularfunctions in the gastrointestinal tract; the intracellular signalingpathways leading to these effects are not clearly defined. Previously,we demonstrated that the human gastric cancer SIIA possesses GRP-R andthat BBS stimulates activator protein-1 (AP-1) gene expression. Thepurpose of our present study was to determine the signaling pathwaysleading to AP-1 induction in SIIA cells. A rapid induction ofc-jun and jun-B gene expression was noted afterBBS treatment; this effect was blocked by specific GRP-R antagonists,indicating that BBS is acting through the GRP-R. The signaling pathwaysleading to increased AP-1 gene expression were delineated using phorbol12-myristate 13-acetate (PMA), which stimulates protein kinase C(PKC)-dependent pathways, by forskolin (FSK), which stimulates proteinkinase A (PKA)-dependent pathways, and by the use of various protein kinase inhibitors. Treatment with PMA stimulated AP-1 gene expression and DNA binding activity similar to the effects noted with BBS; FSKstimulated jun-B expression but produced only minimalincreases of c-jun mRNA and AP-1 binding activity.Pretreatment of SIIA cells with either H-7 or H-8 (primarily PKCinhibitors) inhibited the induction of c-jun andjun-B mRNAs in response to BBS, whereas H-89 (PKA inhibitor)exhibited only minimal effects. Pretreatment with tyrphostin-25, aprotein tyrosine kinase (PTK) inhibitor, attenuated the BBS-mediatedinduction of c-jun and jun-B, but the effect wasnot as pronounced as with H-7. Collectively, our results demonstratethat BBS acts through its receptor to produce a rapid induction of bothc-jun and jun-B mRNA and AP-1 DNA binding activity in the SIIA human gastric cancer. Moreover, this induction ofAP-1, in response to BBS, is mediated through both PKC- and PTK-dependent signal transduction pathways with only minimalinvolvement of PKA. |
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