Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Stepan, VM; Tatewaki, M; Matsushima, M; Dickinson, CJ; del Valle, J; Todisco, A.
Gastrin induces c-fos gene transcription via multiple signaling pathways.
Am J Physiol. 1999; 276(2 Pt 1):G415-G424
Doi: 10.1152/ajpgi.1999.276.2.G415
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- Führende Autor*innen der Med Uni Graz
- Stepan Vinzenz
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- Abstract:
- We previously observed that the trophic actions of gastrin (G17) on the AR42J rat acinar cell line are mediated by mitogen-activated protein kinase (MAPK)-induced c-fos gene transcription via protein kinase C (PKC)-dependent and -independent pathways. In this study, we further investigated the signaling pathways that target c-fos in response to G17. G17 led to a sixfold induction in luciferase activity in cells transfected with plasmids containing the -356+109 sequence of the murine c-fos promoter, which includes the Sis-inducible element (SIE), serum response element (SRE), and the Ca2+/cAMP response element (CRE) regulatory elements. Addition of either the selective PKC inhibitor GF-109203X or the MAPK/extracellular signal-regulated kinase inhibitor PD-98059 resulted in an 80% reduction in luciferase activity. G17 induced the transcriptional activity of both Elk-1 and Sap-1a, transcription factors that bind to the E26 transformation specific (Ets) DNA sequence of the SRE, and this effect was inhibited by both GF-109203X and PD-98059. Point mutations in the Ets sequence led to a 4-fold induction of c-fos transcription stimulated by G17 and to a 1.3-fold induction in response to epidermal growth factor (EGF). In contrast, mutations in the CA rich G (CArG) sequence of the SRE prevented transcriptional activation by both G17 and EGF. G17 induction of the Ets mutant construct was unaffected by either GF-109203X or PD-98059. Because activation of the SRE involves the small GTP-binding protein Rho A, we examined the role of Rho A in G17 induction of c-fos transcription. Inactivation of Rho A by either the specific inhibitor C3 or by expression of a dominant negative Rho A gene inhibited G17 induction of both the wild-type and the Ets mutant constructs by 60%. C3 also inhibited G17-stimulated AR42J cell proliferation. Thus G17 targets the c-fos promoter CArG sequence via Rho A-dependent pathways, and Rho A appears to play an important role in the regulation of the trophic action of G17.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Calcium-Calmodulin-Dependent Protein Kinases - antagonists and inhibitors
- Cells, Cultured -
- Enzyme Inhibitors - pharmacology
- GTP-Binding Proteins - physiology
- Gastrins - pharmacology
- Genes, fos - genetics
- Luciferases - metabolism
- Pancreas - cytology
- Point Mutation - physiology
- Promoter Regions, Genetic - genetics
- Protein Kinase C - antagonists and inhibitors
- Rats -
- Signal Transduction - physiology
- Transcription, Genetic - drug effects Transcription, Genetic - physiology
- Transfection -
- rho GTP-Binding Proteins -
- Find related publications in this database (Keywords)
- cellular proliferation
- early response genes
- protein kinases
- transcriptional regulation
- mitogen-activated protein kinase
- extracellular signal-regulated kinases