Role of Smad and trimeric G protein signaling pathway in liver regeneration

Smad和三聚体G蛋白信号通路在肝再生中的作用

• 批准号: 13670493
• 负责人: YASUDA Hiroshi
• 金额: $ 0.96万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670493/
• 关键词: liver regeneration; Smad; activin; norepinephrine; アクチビン; PKC; Smad

Activin A induces growth arrest of rat hepatocytes in vitro and in vivo. The α_1-adrenergic agonist, norepinephrine (NE), enhances epidermal growth factor (EGF)-stimulated DNA synthesis and inhibits activin A-induced growth inhibition, but the mechanisms of these actions are unclear. Smad proteins have recently been identified as intracellular signaling mediators of transforming growth factor (TGF) -β family members. In the present study, we explored how NE modulates the Smad signaling pathway in rat cultured hepatocytes. We demonstrate that NE inhibits activin A-induced nuclear accumulation of Smad2/3, and that NE rapidly induces inhibitory Smad7 mRNA expression. Infection of Smad7 adenovirus into rat hepatocytes inhibited activin A-induced nuclear accumulation of Smad2/3, enhanced EGF-stimulated DNA synthesis and abolished the growth inhibitory effect of activin A. We also demonstrated that the induction of Smad7 by NE is dependent on nuclear factor-KB (NF-KB). The amount of active NF-KB complex rapidly increased after NE treatment. Preincubation of the cells with an NF-KB pathway inhibitor N-tosyl-L-phenylalanine chloromethyl ketone abolished the NE-induced Smad7 expression. These results indicate a mechanism of transmodulation between the Smad and trimeric G protein signaling pathways in rat hepatocytes.

激活素A在体外和体内诱导大鼠肝细胞生长停滞。α_1肾上腺素能激动剂去甲肾上腺素（NE）能增强表皮生长因子（EGF）刺激的DNA合成，抑制激活素A诱导的生长抑制，但其作用机制尚不清楚。Smad蛋白是转化生长因子β（TGF-β）家族成员的细胞内信号传导介质。在本研究中，我们探讨了NE如何调节Smad信号通路在大鼠培养的肝细胞。我们表明，NE抑制激活素A诱导的Smad 2/3的核积累，NE迅速诱导抑制Smad 7 mRNA的表达。Smad 7腺病毒感染大鼠肝细胞可抑制激活素A诱导的Smad 2/3核内聚集，增强EGF刺激的DNA合成，并消除激活素A的生长抑制作用。我们还证明了NE对Smad 7的诱导依赖于核因子-κ B（NF-κ B）。NE处理后，活性NF-κ B复合物的量迅速增加。用NF-κ B通路抑制剂N-甲苯磺酰-L-苯丙氨酸氯甲基酮预孵育细胞，可消除NE诱导的Smad 7表达。这些结果表明，在大鼠肝细胞中的Smad和三聚体G蛋白信号通路之间的transmodulation的机制。

项目成果

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