Antagonism of glucocorticoid receptor transactivity and cell growth inhibition by transforming growth factor-β through AP-1-mediated transcriptional repression

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• 作者：Periyasamy ; Sumudra ; Sá ; nchez ; Edwin R.
• 关键词：Steroid receptor ; Glucocorticoid ; Transforming growth factor-&#946 ; AP-1 ; Cell growth
• 刊名：The International Journal of Biochemistry and Cell Biology
• 出版年：2002
• 期刊代码：127_13572725
• 类别：med
• 出版时间：December, 2002
• 卷：34
• 期：1
• 页码：1571-1585
• 文件大小：527 K

摘要

We have examined the interaction of the glucocorticoid receptor (GR) and transforming growth factor-β (TGF-β) signal pathways because of their mutual involvement in the regulation of cell growth, development and differentiation. Most studies of this cross-talk event have focused on the effects of glucocorticoids (GCs) on TGF-β responses. In this work, we show that TGF-β can antagonize dexamethasone (Dex)-mediated growth suppression in mouse fibrosarcoma L929 cells. TGF-β also repressed GR-mediated reporter (pMMTV-CAT) gene expression in a concentration-dependent manner, with an IC₅₀ of 5ng/ml of TGF-β. Maximal inhibition (76%) was observed at 10ng/ml of TGF-β. Conversely, Dex inhibited TGF-β-mediated promoter (p3TP-Lux) activity in these same cells. As TGF-β inhibition of GR-mediated gene expression occurred after Dex-mediated nuclear translocation of GR, we conclude that TGF-β inhibition of GR signaling occurs at the level of GR-mediated transcription activity. However, TGF-β did not repress GR-mediated gene expression using the pGRE₂E1B-CAT minimal promoter construct, suggesting that TGF-β did not inhibit intrinsic GR activity but, rather, required DNA-binding factor(s) distinct from GR. As the MMTV promoter contains several putative AP-1 binding sites, we hypothesized that AP-1, a transcription factor composed of c-jun and c-fos proteins, might be involved in the TGF-β inhibition of GR functions. Curcumin, a potent inhibitor of AP-1 expression, completely abolished the inhibitory effect of TGF-β on GR-mediated gene expression without affecting GR activity in the absence of TGF-β, and this drug blocked TGF-β-induced binding of AP-1 to a response element derived from the MMTV sequence. Furthermore, curcumin abolished TGF-β inhibition of Dex-induced growth suppression. Taken as a whole, our data suggest that TGF-β can antagonize the growth inhibitory properties of GR by blocking GR transactivity at complex promoters through a mechanism involving transcriptional repression by DNA-bound AP-1.