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Gastrin-mediated activation of cyclin D1 transcription involves β-catenin and CREB pathways in gastric cancer cells

Oncogene volume 23, pages 3689–3699 (2004)Cite this article

Abstract

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 G1-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 β-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 β-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 β-catenin and CREB pathways.

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Abbreviations

β-Gal:

β-galactosidase

CBP:

CREB-binding protein

CCKB:

cholecystokinin B

ChIP:

chromatin immunoprecipitation

CRE:

cyclic AMP response element

CREB:

CRE-binding protein

dnTCF4:

dominant-negative TCF4

FACS:

fluorescence-activated cell sorter

G-17:

amidated gastrin

GI:

gastrointestinal

H. pylori:

Helicobacter pylori

LEF:

lymphoid enhancer factor

PCNA:

proliferating cell nuclear antigen

PI3Kinase:

phosphatidylinositol 3-kinase

TCF:

T-cell factor

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Acknowledgements

We are grateful to Drs Roel Nusse for providing the retroviral vector pHYTCAxin-myc, Hans C Clevers for dnTCF4 cDNA, Stephen W Byers for wild-type β-catenin cDNA, Richard Goodman for KCREB cDNA and Bert Vogelstein for pGL3OT and pGL3OF. We also thank our colleagues Drs Ajay Rana and Guri Tzivion for providing reagents and helpful suggestions, David Dostal for statistical analysis, David Morgan for Flow Cytometry and Suchitra Joshi for immunofluorescence studies.

This work was supported by Departmental Start-up Funds from Texas A&M University to BR, by grants from NIH to RGP (CA70896, CA75503, CA86072), to CA (AG2033), to MMW (KD53158) and to KMB (HL44883, HL54583). Work conducted at the Lombardi Cancer Center was supported by the NIH Cancer Center Core grant.

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Authors and Affiliations

  1. Division of Molecular Cardiology, The Texas A&M University System Health Science Center, College of Medicine, Temple, 76504, TX, USA

    Anamika Pradeep, Chandan Sharma, Pradeep Sathyanarayana, Kenneth M Baker & Basabi Rana

  2. Lombardi Cancer Center, Georgetown University Medical Center, Washington, 20057, DC, USA

    Chris Albanese & Richard G Pestell

  3. Gastrointestinal Division, University of Massachusetts Medical School, Worcester, 01605-2324, MA, USA

    John V Fleming & Timothy C Wang

  4. Section of Gastroenterology, Boston Medical Center, Boston, 02118, MA, USA

    M Michael Wolfe

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  1. Anamika Pradeep
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Correspondence to Basabi Rana.

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Pradeep, A., Sharma, C., Sathyanarayana, P. et al. Gastrin-mediated activation of cyclin D1 transcription involves β-catenin and CREB pathways in gastric cancer cells. Oncogene 23, 3689–3699 (2004). https://doi.org/10.1038/sj.onc.1207454

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