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The gep oncogenes, Gα12 and Gα13, upregulate the transforming growth factor-β1 gene

Oncogene volume 28, pages 1230–1240 (2009)Cite this article

Abstract

Transforming growth factor-β1 (TGFβ1) plays a role in neoplastic transformation and transdifferentiation. Gα12 and Gα13, referred to as the gep oncogenes, stimulate mitogenic pathways. Nonetheless, no information is available regarding their roles in the regulation of the TGFβ1 gene and the molecules linking them to gene transcription. Knockdown or knockout experiments using murine embryonic fibroblasts and hepatic stellate cells indicated that a Gα12 and Gα13 deficiency reduced constitutive, auto-stimulatory or thrombin-inducible TGFβ1 gene expression. In contrast, transfection of activated mutants of Gα12 and Gα13 enabled the knockout cells to promote TGFβ1 induction. A promoter deletion analysis suggested that activating protein 1 (AP-1) plays a role in TGFβ1 gene transactivation, which was corroborated by the observation that a deficiency of the G-proteins decreased the AP-1 activity, whereas their activation enhanced it. Moreover, mutation of the AP-1-binding site abrogated the ability of Gα12 and Gα13 to induce the TGFβ1 gene. Transfection of a dominant-negative mutant of Rho or Rac, but not Cdc42, prevented gene transactivation and decreased AP-1 activity downstream of Gα12 and Gα13. In summary, Gα12 and Gα13 regulate the expression of the TGFβ1 gene through an increase in Rho/Rac-dependent AP-1 activity, implying that the G-protein-coupled receptor (GPCR)-Gα12 pathway is involved in the TGFβ1-mediated transdifferentiation process.

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Acknowledgements

We thank Dr SC Brooks III for helpful discussion and English editing. This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (No. R11-2007-107-01001-0), Korea.

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  1. S J Lee and J W Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Innovative Drug Research Center for Metabolic and Inflammatory Disease, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea

    S J Lee, J W Yang, I J Cho, W D Kim, M K Cho & S G Kim

  2. College of Oriental Medicine, Dongguk University, Kyungju, Korea

    M K Cho

  3. Department of Pharmacology and Institute of Biomedical Science, College of Medicine, Hanyang University, Seoul, Korea

    C H Lee

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Lee, S., Yang, J., Cho, I. et al. The gep oncogenes, Gα12 and Gα13, upregulate the transforming growth factor-β1 gene. Oncogene 28, 1230–1240 (2009). https://doi.org/10.1038/onc.2008.488

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