Gastrin-mediated activation of cyclin D1 transcription involves beta-catenin and CREB pathways in gastric cancer cells.
Gastrin and its precursors promote proliferation in different gastrointestinal cells. Since mature, amidated gastrin (G-17) can induce cyclin D1, we determined whether G-17-mediated induction of cyclin D1 transcription involved Wnt signaling and CRE-binding protein (CREB) pathways. Our studies indicate that G-17 induces protein, mRNA expression and transcription of the G(1)-specific marker cyclin D1, in the gastric adenocarcinoma cell line AGSE (expressing the gastrin/cholecystokinin B receptor). This was associated with an increase in steady-state levels of total and nonphospho beta-catenin and its nuclear translocation, indicating the activation of the Wnt-signaling pathway. In addition, G-17-mediated increase in cyclin D1 transcription was significantly attenuated by axin or dominant-negative (dn) T-cell factor 4(TCF4), suggesting crosstalk of G-17 with the Wnt-signaling pathway. Mutational analysis indicated that this effect was mediated through the cyclic AMP response element (CRE) (predominantly) and the TCF sites in the cyclin D1 promoter, which was also inhibited by dnCREB. Furthermore, G-17 stimulation resulted in increased CRE-responsive reporter activity and CREB phosphorylation, indicating an activation of CREB. Chromatin immunoprecipitation studies revealed a G-17-mediated increase in the interaction of beta-catenin with cyclin D1 CRE, which was attenuated by dnTCF4 and dnCREB. These results indicate that G-17 induces cyclin D1 transcription, via the activation of beta-catenin and CREB pathways.
Pradeep
Anamika
A
Division of Molecular Cardiology, The Texas A and M University System Health Science Center, College of Medicine, Temple, TX 76504, USA.
Sharma
Chandan
C
Sathyanarayana
Pradeep
P
Albanese
Chris
C
Fleming
John V
JV
Wang
Timothy C
TC
Wolfe
M Michael
MM
Baker
Kenneth M
KM
Pestell
Richard G
RG
Rana
Basabi
B
D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D016193:G1 Phase / Q000502:physiology; D005755:Gastrins / Q000378:metabolism*; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016196:S Phase / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013274:Stomach Neoplasms / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D003598:Cytoskeletal Proteins; D005755:Gastrins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D019938:Cyclin D1; C013550:gastrin 17