Requirement of Ras-Dependent Pathways for Activation of the Transforming Growth Factor 3 Promoter by Estradiol

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Abstract
It has been previously observed that the transforming growth factorβ 3 (TGFβ3) gene can be activated by both estradiol (E2) and selective estrogen receptor modulators (SERMs) in vivo but that only SERMs have a potent stimulatory effect on the TGFβ3 promoter in cultured cells. We demonstrate in this report that E2 can act also as a potent inducer of the TGFβ3 promoter via a novel and specific estrogen receptor (ER)α-mediated mechanism. Our results show that treatment with epidermal growth factor or transfection of a constitutively active Ras mutant allows E2 to induce the TGFβ3 promoter via ERα in cotransfected HeLa and osteosarcoma MG63 cells. Both protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) inhibitors can block the combined stimulatory effect of E2 and epidermal growth factor/Ras. However, E2 induction of the TGFβ3 promoter was found to be unaffected by mutation of ERα serine 118, a well-characterized target of MAPK. Progressive deletion analysis of the ERα amino-terminal region delineated three separate domains modulating the E2/activated Ras response, revealing a complex functional organization of the ERα A/B domain required for regulation of the TGFβ3 promoter. In addition, PKC and MAPK inhibitors had no effect on the induction of TGFβ3 promoter activity by the SERM EM-652. These results indicate that induction of the TGFβ3 promoter by the E2/ERα complex requires the concomitant activation of PKC and MAPK signaling and provide a novel framework for the design of more effective estrogen-based therapeutic strategies.

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