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

Hong Jin Kim, B. Mark Evers, David A. Litvak, Mark Hellmich, Courtney Townsend

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume279
Issue number2 48-2
StatePublished - 2000

Fingerprint

Bombesin
Transcription Factor AP-1
Stomach Neoplasms
Genes
Gastrin-Releasing Peptide
Protein Kinase Inhibitors
Gene expression
Cyclic AMP-Dependent Protein Kinases
Protein Kinase C
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
Gene Expression
Colforsin
Protein-Tyrosine Kinases
Messenger RNA
Acetates
jun Genes
Bombesin Receptors
Signal transduction
Protein C Inhibitor
DNA

Keywords

  • Activator protein-1
  • Gastrin-releasing peptide
  • Protein kinase C
  • Protein tyrosine kinase

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology
  • Physiology (medical)

Cite this

Signaling mechanisms regulating bombesin-mediated AP-1 gene induction in the human gastric cancer SIIA. / Kim, Hong Jin; Evers, B. Mark; Litvak, David A.; Hellmich, Mark; Townsend, Courtney.

In: American Journal of Physiology - Cell Physiology, Vol. 279, No. 2 48-2, 2000.

Research output: Contribution to journalArticle

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AU - Townsend, Courtney

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