Activin A mediates growth inhibition and cell cycle arrest through smads in human breast cancer cells
Activin A mediates growth inhibition and cell cycle arrest through smads in human breast cancer cells
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DOI：
10.1158/0008-5472.can-04-3553
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发表时间：
2005-09-01
期刊：
影响因子：
11.2
通讯作者：
Woodruff, TK
中科院分区：
文献类型：
--
作者：
Burdette, JE;Jeruss, JS;Woodruff, TK
转化生长因子-β(转化生长因子-β)超家族生长因子参与多种生理活动，包括细胞周期调节。激活素是抑制乳腺癌细胞增殖的转化生长因子-β超家族成员之一。激活素通过与其I型和IOTA受体相互作用来诱导细胞内信号分子Smads的磷酸化来发挥作用。Smads以细胞和组织特有的方式调节许多基因的转录。本研究探讨激活素A在乳腺癌细胞生长调控中的作用。激活素在T47D乳腺癌细胞中刺激Smad反应启动子p3TP，是对照的2倍。激活素在72小时后抑制T47D乳腺癌细胞的细胞增殖，这种作用可以通过与激活素I型受体抑制剂SB431542孵育而被取消。激活素使T47D细胞停滞于Go-G期，细胞周期时相。Smad2和Smad3在激活素作用下被磷酸化，并聚集在处理的T47D细胞的细胞核中。腺病毒Smad3感染T47D细胞后，细胞周期停滞并激活p3TP-荧光素酶，而显性阴性的Smad3则阻断激活素介导的细胞周期停滞和基因转录。激活素维持参与细胞周期控制的p21和p27细胞周期蛋白依赖性激酶抑制物的表达，增强p15的表达，降低细胞周期蛋白A的表达，并降低视网膜母细胞瘤(RB)蛋白的磷酸化。Smad3的过表达概括了激活素诱导的p15表达，并抑制了细胞周期蛋白A和Rb的磷酸化。这些数据表明，激活素A抑制乳腺癌细胞的增殖，并激活负责启动细胞周期停滞的Smads。
The transforming growth factor-beta (TGF-beta) superfamily of growth factors is responsible for a variety of physiologic actions, including cell cycle regulation. Activin is a member of the TGF-beta superfamily that inhibits the proliferation of breast cancer cells. Activin functions by interacting with its type I and type Iota Iota receptors to induce phosphorylation of intracellular signaling molecules known as Smads. Smads regulate transcription of many genes in a cell- and tissue-specific manner. In this study, the role of activin A in growth regulation of breast cancer cells was investigated. Activin stimulated the Smad-responsive promoter, p3TP, 2-fold over control in T47D breast cancer cells. Activin inhibited cellular proliferation of T47D breast cancer cells after 72 hours, an effect that could be abrogated by incubation with the activin type I receptor inhibitor, SB431542. Activin arrested T47D cells in the GO-G, cell cycle phase. Smad2 and Smad3 were phosphorylated in response to activin and accumulated in the nucleus of treated T47D cells. Infection of T47D cells with adenoviral Smad3 resulted in cell cycle arrest and activation of p3TP-luciferase, whereas a adenoviral dominant-negative Smad3 blocked activin-mediated cell cycle arrest and gene transcription. Activin maintained expression of p21 and p27 cyclin-dependent kinase inhibitors involved in cell cycle control, enhanced expression of p15, reduced cyclin A expression, and reduced phosphorylation of the retinoblastoma (Rb) protein. Smad3 overexpression recapitulated activin-induced p15 expression and repression of cyclin A and Rb phosphorylation. These data indicate that activin A inhibits breast cancer cellular proliferation and activates Smads responsible for initiating cell cycle arrest.