The gep oncogenes, G alpha(12) and G alpha(13), upregulate the transforming growth factor-beta 1 gene

초록

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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