Smad7 induces turnorigenicity by blocking TGF-β-induced growth inhibition and apoptosis
Smad7 induces turnorigenicity by blocking TGF-β-induced growth inhibition and apoptosis
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DOI：
10.1016/j.yexcr.2005.03.009
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发表时间：
2005-07-01
影响因子：
3.7
通讯作者：
Datta, PK
中科院分区：
文献类型：
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作者：
Halder, SK;Beauchamp, RD;Datta, PK
Smad蛋白在细胞外多肽的转化生长因子β（TGF-β）超家族的细胞内信号传导中起关键作用，所述细胞外多肽启动信号传导以调节多种生物过程。抑制性Smad（Smad 7）已显示作为TGF-β家族信号传导的细胞内拮抗剂起作用，并且在几种癌症中上调。为了确定Smad 7介导的TGF-β信号传导阻断的效果，我们在源自人结肠腺癌的TGF-β敏感的、分化良好的和非致瘤性的细胞系FET中稳定表达Smad 7。Smad 7通过阻断Smad 2/3和Smad 4之间的复合物形成来抑制TGF-β诱导的转录反应。Smad 7对TGF-β诱导的p38 MAPK和ERK的激活没有影响，但它能阻断TGF-β对Akt的磷酸化，增强TGF-β诱导的c-Jun的磷酸化。Smad 7通过阻止TGF-β诱导的G1期阻滞来阻断TGF-β诱导的生长抑制。Smad 7抑制TGF β介导的c-Myc、CDK 4和Cyclin D1的下调，并抑制p21（Cip 1）的表达。因此，Smad 7抑制TGF-β介导的Rb磷酸化下调。此外，Smad 7抑制这些细胞的凋亡。总之，Smad 7可以通过阻断TGF-β诱导的生长抑制和通过抑制细胞凋亡来增加FET细胞的turnorigenicity。因此，这项研究提供了一种机制，通过这种机制，一部分人类结直肠肿瘤可能对TGF-β的肿瘤抑制作用变得难以抵抗，这可能导致肿瘤发生率增加。(c)2005年爱思唯尔公司All rights reserved.
Smad proteins play a key role in the intracellular signaling of the transforming growth factor beta (TGF-beta) superfamily of extracellular polypeptides that initiate signaling to regulate a wide variety of biological processes. The inhibitory Smad, Smad7, has been shown to function as intracellular antagonists of TGF-beta family signaling and is upregulated in several cancers. To determine the effect of Smad7-mediated blockade of TGF-beta signaling, we have stably expressed Smad7 in a TGF-beta-sensitive, well-differentiated, and non-tumorigenic cell line, FET, that was derived from human colon adenocarcinoma. Smad7 inhibits TGF-beta-induced transcriptional responses by blocking complex formation between Smad 2/3 and Smad4. While Smad7 has no effect on TGF-beta-induced activation of p38 MAPK and ERK, it blocks the phosphorylation of Akt by TGF-beta and enhances TGF-beta-induced phosphorylation of c-Jun. FET cells expressing Smad7 show anchorage-independent growth and enhance tumorigenicity in athyrnic nude rnice. Smad7 blocks TGF-beta-induced growth inhibition by preventing TGF-beta-induced G1 arrest. Smad7 inhibits TGF beta-mediated downregulation of c-Myc, CDK4, and Cyclin D1, and suppresses tile expression of p21(Cip1). As a result, Smad7 inhibits TGF-beta-mediated downregulation of Rb phosphorylation. Furthermore, Smad7 inhibits the apoptosis of these cells. Together, Smad7 may increase the turnorigenicity of FET cells by blocking TGF-beta-mduced growth inhibition and by inhibiting apoptosis. Thus, this study provides a mechanism by which a portion of human colorectal turnors may become refractory to turriorsuppressive actions of TGF-beta that might result in increased tumorigenicity. (c) 2005 Elsevier Inc. All rights reserved.