Regulation and actions of Smad7 in the modulation of activin, inhibin, and transforming growth factor-β signaling in anterior pituitary cells
Regulation and actions of Smad7 in the modulation of activin, inhibin, and transforming growth factor-β signaling in anterior pituitary cells
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DOI：
10.1210/en.142.3.1065
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发表时间：
2001-03-01
期刊：
影响因子：
4.8
通讯作者：
Vale, WW
中科院分区：
文献类型：
--
作者：
Bilezikjian, LM;Corrigan, AZ;Vale, WW
激活素和转化生长因子-β是垂体前叶功能的重要自分泌、旁分泌和内分泌调节因子。激活素调节大多数垂体细胞，催乳素是转化生长因子β的靶标。Smad2和Smad3是激活素/转化生长因子β信号转导的两种细胞介质，而Smad7则是该通路的可诱导的负调节因子。本研究旨在探讨Smad7对垂体的调节作用。激活素A可使大鼠垂体前叶(RAP)、克隆性促性腺激素(αT3-1和LβT2)和促肾上腺皮质激素(ATT20)细胞的Smad7信使核糖核酸水平迅速而短暂地升高，EC50为0.1-0.2 nM。在RAP细胞中，激活素A或转化生长因子β1具有相同的相加作用。卵泡抑素可以结合和失活激活素，阻止激活素诱导的Smad7。抑制素A部分拮抗激活素A，可能反映促性腺激素的选择性作用。这种拮抗作用在αT_3-1和LβT_2促性腺激素中也很明显。Forskolin对RAP细胞无明显作用，但使αT3-1细胞Smad7mRNA水平升高，而LβT2细胞Smad7mRNA水平降低。瞬时转染Smad7和激活素/转化生长因子β反应报告基因3TPLux可阻断激活素介导的启动子在αT3-1和AtT20细胞中的激活。在表达内源性卵泡抑素mRNA的αT3-1细胞中，卵泡抑素-荧光素酶报告基因RFS(Rin3)-Luc被激活素A转录激活，或者当与构成活性的ActRIB[Alk4(T>；D)]、Smad2或Smad3共转染时。Smad7可阻断激活素A或Alk4(T>；D)对RFS(Rin3)-Luc的激活。综上所述，这些结果表明Smad7在调节脑下垂体中的活动/转化生长因子β信号方面发挥了作用。
Activins and transforming growth factor-beta (TGF beta) are crucial autocrine, paracrine, and endocrine modulators of anterior pituitary function. Activins regulate most pituitary cells and lactotropes are targets of TGF beta. Smad2 and Smad3 are two cellular mediators of activin/TGF beta signaling, whereas Smad7 is as an inducible, negative modulator of the pathway. This study was undertaken to evaluate Smad7 regulation in the pituitary. Activin A rapidly and transiently increased Smad7 messenger RNA (mRNA) levels of rat anterior pituitary (RAP), clonal gonadotrope (alpha T3-1 and L beta T2), and corticotrope (AtT20) cells with an EC50 of 0.1-0.2 nM. In RAP cells, activin A or TGF beta1 had equivalent effects that were additive. Follistatin, known to bind and inactivate activins, prevented Smad7 induction by activin. Inhibin A partially antagonized activin A, perhaps reflecting gonadotrope-selective actions. This antagonism was also evident with alpha T3-1 and L beta T2 gonadotropes. Forskolin had no measurable effect in RAP cells, but increased Smad7 mRNA levels in alpha T3-1 cells and decreased them in L beta T2 cells. Transient transfection of Smad7 along with 3TPLux, an activin/TGF beta -responsive reporter, blocked activin-mediated promoter activation in alpha T3-1 and AtT20 cells. In alpha T3-1 cells, which express endogenous follistatin mRNA, a follistatin-luciferase reporter, rFS(rin3)-Luc, was transcriptionally activated by activin A, or when cotransfected with a constitutively active ActRIB [Alk4(T>D)], Smad2, or Smad3. Smad7 blocked rFS(rin3)-Luc activation by activin A or Alk4(T>D). Together, these results point to a role of Smad7 in modulating activity/TGF beta signaling in the pituitary.