Transcriptional regulation of Smad2 is required for enhancement of TGFβ/Smad signaling by TGFβ inducible early gene
Transcriptional regulation of Smad2 is required for enhancement of TGFβ/Smad signaling by TGFβ inducible early gene
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DOI：
10.1002/jcb.10299
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发表时间：
2002-01-01
影响因子：
4
通讯作者：
Spelsberg, TC
中科院分区：
文献类型：
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作者：
Johnsen, SA;Subramaniam, M;Spelsberg, TC
TGFbeta 诱导早期基因 (TIEG) 是一种新型 Kruppel 样转录抑制因子，最近被证明可以通过抑制抑制性 Smad7 来缓解负反馈，从而增加 TGFbeta/Smad signala I 转导途径的活性。有趣的是，虽然 Smad7 是最大限度增强 TGFbeta/Smad 信号传导所必需的，但我们观察到 TIEG 在没有 Smad7 的情况下仍然能够增加 Smad 通路活性。此外，虽然已知 Smad7 可以阻断 TGFbeta 和骨形态发生蛋白 (BMP) 信号传导，但我们观察到 TIEG 仅特异性增强 TGFbeta 途径。同样，虽然 TIEG 和相关的 Kruppel 样因子 FKLF2 均抑制 Smad7 转录，但只有 TIEG 能够增强 Smad 信号传导。为了确定对于 Smad 通路活性增强重要的 TIEG 额外调控靶点，我们进行了微阵列分析，并将 Smad2 鉴定为 TIEG 靶基因。我们现在证明 TIEG 会增加 Smad2 基因的转录，但不会增加 Smad3 或 Smad4 基因的转录。此外，虽然 TGFbeta/Smad 通路在 Smad2 缺失细胞中保持完整，但 TIEG 对 Smad 信号传导的增强作用显着减弱。因此，我们提出了一种新模型，TIEG 通过抑制抑制性 Smad7 和激活 Smad2 的双重机制增强 Smad 信号传导。
TGFbeta inducible early gene (TIEG) is a novel Kruppel-like transcriptional repressor that was recently shown to increase the activity of the TGFbeta/Smad signa I transduction pathway by relieving negative feedback through repression of the inhibitory Smad7. Interestingly, while Smad7 is required for maximal enhancement of TGFbeta/Smad signaling, we observe that TIEG is still capable of increasing Smad pathway activity in the absence of Smad7. Furthermore, while Smad7 is known to block both TGFbeta and bone morphogenetic protein (BMP) signaling, we observe that TIEG specifically enhances only the TGFbeta pathway. Similarly, while both TIEG and the related Kruppel-like factor, FKLF2, repress Smad7 transcription, only TIEG is capable of enhancing Smad signaling. In order to identify additional regulatory targets of TIEG important for this enhancement of the Smad pathway activity, we performed microarray analysis and identified Smad2 as a TIEG target gene. We now show evidence that TIEG increases transcription of the Smad2 gene but not the Smad3 or Smad4 genes. Furthermore, while the TGFbeta/Smad pathway remains intact in Smad2 null cells, TIEG enhancement of Smad signaling is dramatically reduced. Thus we propose a new model whereby TIEG enhances Smad signaling by a dual mechanism involving both the repression of the inhibitory Smad7 as well as the activation of Smad2.