Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

Logo MUG-Forschungsportal

Gewählte Publikation:

Todisco, A; Takeuchi, Y; Urumov, A; Yamada, J; Stepan, VM; Yamada, T.
Molecular mechanisms for the growth factor action of gastrin.
Am J Physiol. 1997; 273(4 Pt 1):G891-G898 [OPEN ACCESS]
Web of Science PubMed FullText


Autor/innen der Med Uni Graz:
Stepan Vinzenz

Dimensions Citations:

Plum Analytics:
We have previously observed that gastrin has a cholecystokinin B (CCK-B) receptor-mediated growth-promoting effect on the AR42J rat pancreatic acinar cell line and that this effect is paralleled by induction of expression of the early response gene c-fos. We undertook these experiments to elucidate the mechanism for induction of c-fos and the linkage of this action to the trophic effects of gastrin. Gastrin (0.1-10 nM) dose dependently induced luciferase activity in AR42J cells transfected with a construct consisting of a luciferase reporter gene coupled to the serum response element (SRE) of the c-fos promoter. This effect was blocked by the specific CCK-B receptor antagonist D2 but not by the specific CCK-A receptor antagonist L-364,718 or by pertussis toxin, indicating that gastrin targets the SRE via specific CCK-B receptors through a mechanism independent of Gi. Inhibition of protein kinase C (PKC) either by prolonged (24 h) exposure of the cells to the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (100 nM) or by incubation with the selective inhibitor GF-109203X (3.5 microM) resulted in an 80% reduction in luciferase activity. Similar results were observed in the presence of the specific extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor PD-98059 (50 microM). We measured ERK2 activity in AR42J cells via in-gel kinase assays and observed that gastrin (1 pM-100 nM) induced ERK2 enzyme activity in a dose-dependent manner. Addition of GF-109203X and PD-98059, either alone or in combination, produced, respectively, partial and total inhibition of gastrin-induced ERK2 activity. Gastrin induction of ERK2 activity also resulted in a threefold increase in the transcriptional activity of Elk-1, a factor known to bind to the c-fos SRE and to be phosphorylated and activated by ERK2. PD-98059 blocked the growth-promoting effect of gastrin on the AR42J cells, demonstrating that this effect depends on activation of MEK. Our data lead us to conclude that the trophic actions of gastrin are mediated by ERK2-induced c-fos gene expression via PKC-dependent and -independent pathways.
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Benzodiazepinones - pharmacology
Calcium-Calmodulin-Dependent Protein Kinases - metabolism
Cell Line -
DNA-Binding Proteins -
Devazepide -
Enzyme Inhibitors - pharmacology
Flavonoids - pharmacology
Gastrins - pharmacology
Genes, fos -
Hormone Antagonists - pharmacology
Humans -
Indoles - pharmacology
Luciferases - biosynthesis
Maleimides - pharmacology
Mitogen-Activated Protein Kinase 1 -
Pancreas -
Pertussis Toxin -
Promoter Regions, Genetic -
Protein Kinase C - antagonists and inhibitors
Proto-Oncogene Proteins - biosynthesis
Proto-Oncogene Proteins c-fos - biosynthesis
Rats -
Receptor, Cholecystokinin A -
Receptor, Cholecystokinin B -
Receptors, Cholecystokinin - antagonists and inhibitors Receptors, Cholecystokinin - physiology
Recombinant Proteins - biosynthesis
Tetradecanoylphorbol Acetate - pharmacology
Transcription Factors - biosynthesis
Transcription, Genetic - drug effects
Transfection -
Virulence Factors, Bordetella - pharmacology
ets-Domain Protein Elk-1 -

Find related publications in this database (Keywords)
cholecystokinin-B receptor
cellular proliferation
early response genes
protein kinases
transcriptional regulation
mitogen-activated protein kinase
extracellular signal-regulated protein kinases
© Med Uni Graz Impressum