Signaling mechanisms regulating bombesin-mediated AP-1 gene induction in the human gastric cancer SIIA

2  Department of Surgery, The University of Texas Medical Branch, Galveston, Texas 77555; 1  Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637; and 3  University of California, Davis-East Bay, Oakland, California 94602 The hormone bombesin (BBS) and its mammali...

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Published in:American Journal of Physiology: Cell Physiology 2000-08, Vol.279 (2), p.C326-C334
Main Authors: Kim, Hong Jin, Evers, B. Mark, Litvak, David A, Hellmich, Mark R, Townsend, Courtney M., Jr
Format: Article
Language:English
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Summary:2  Department of Surgery, The University of Texas Medical Branch, Galveston, Texas 77555; 1  Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637; and 3  University of California, Davis-East Bay, Oakland, California 94602 The hormone bombesin (BBS) and its mammalian equivalent gastrin-releasing peptide (GRP) act through specific GRP receptors (GRP-R) to affect multiple cellular functions in the gastrointestinal tract; the intracellular signaling pathways leading to these effects are not clearly defined. Previously, we demonstrated that the human gastric cancer SIIA possesses GRP-R and that BBS stimulates activator protein-1 (AP-1) gene expression. The purpose of our present study was to determine the signaling pathways leading to AP-1 induction in SIIA cells. A rapid induction of c- jun and jun -B gene expression was noted after BBS treatment; this effect was blocked by specific GRP-R antagonists, indicating that BBS is acting through the GRP-R. The signaling pathways leading to increased AP-1 gene expression were delineated using phorbol 12-myristate 13-acetate (PMA), which stimulates protein kinase C (PKC)-dependent pathways, by forskolin (FSK), which stimulates protein kinase 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; FSK stimulated jun -B expression but produced only minimal increases of c- jun mRNA and AP-1 binding activity. Pretreatment of SIIA cells with either H-7 or H-8 (primarily PKC inhibitors) inhibited the induction of c- jun and jun -B mRNAs in response to BBS, whereas H-89 (PKA inhibitor) exhibited only minimal effects. Pretreatment with tyrphostin-25, a protein tyrosine kinase (PTK) inhibitor, attenuated the BBS-mediated induction of c- jun and jun -B, but the effect was not as pronounced as with H-7. Collectively, our results demonstrate that BBS acts through its receptor to produce a rapid induction of both c- jun and jun -B mRNA and AP-1 DNA binding activity in the SIIA human gastric cancer. Moreover, this induction of AP-1, in response to BBS, is mediated through both PKC- and PTK-dependent signal transduction pathways with only minimal involvement of PKA. gastrin-releasing peptide; protein kinase C; protein tyrosine kinase; activator protein-1
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.2000.279.2.C326