The gep oncogenes, G alpha(12) and G alpha(13), upregulate the transforming growth factor-beta 1 gene
- Authors
- Lee, Sung Joong; Yang, Jin Won; Cho, Il-Je; Kim, Wondong; Cho, Min Kyung; Lee, Chang Ho; Kim, Sang Geon
- Issue Date
- Mar-2009
- Publisher
- SPRINGERNATURE
- Keywords
- G alpha(12) members; transforming growth factor-beta 1; hepatic stellate cell; activating protein 1
- Citation
- ONCOGENE, v.28, no.9, pp.1230 - 1240
- Indexed
- SCIE
SCOPUS
- Journal Title
- ONCOGENE
- Volume
- 28
- Number
- 9
- Start Page
- 1230
- End Page
- 1240
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/177192
- DOI
- 10.1038/onc.2008.488
- ISSN
- 0950-9232
- Abstract
- Transforming growth factor-beta 1 (TGF beta 1) plays a role in neoplastic transformation and transdifferentiation. G alpha(12) and G alpha(13), referred to as the gep oncogenes, stimulate mitogenic pathways. Nonetheless, no information is available regarding their roles in the regulation of the TGF beta 1 gene and the molecules linking them to gene transcription. Knockdown or knockout experiments using murine embryonic fibroblasts and hepatic stellate cells indicated that a G alpha(12) and G alpha(13) deficiency reduced constitutive, auto-stimulatory or thrombin-inducible TGF beta 1 gene expression. In contrast, transfection of activated mutants of G alpha(12) and G alpha(13) enabled the knockout cells to promote TGF beta 1 induction. A promoter deletion analysis suggested that activating protein 1 (AP-1) plays a role in TGF beta 1 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 G alpha(12) and G alpha(13) to induce the TGF beta 1 gene. Transfection of a dominant-negative mutant of Rho or Rac, but not Cdc42, prevented gene transactivation and decreased AP-1 activity downstream of G alpha 12 and G alpha 13. In summary, G alpha 12 and G alpha 13 regulate the expression of the TGF beta 1 gene through an increase in Rho/Rac-dependent AP-1 activity, implying that the G-protein-coupled receptor (GPCR)-G alpha(12) pathway is involved in the TGF beta 1-mediated transdifferentiation process.
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