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 |
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Main Authors: | , , , , |
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 |
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ISSN: | 0363-6143 1522-1563 |
DOI: | 10.1152/ajpcell.2000.279.2.C326 |