Transcription activation of FLRG and follistatin by activin A, through Smad proteins, participates in a negative feedback loop to modulate activin A function
Transcription activation of FLRG and follistatin by activin A, through Smad proteins, participates in a negative feedback loop to modulate activin A function
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DOI：
10.1038/sj.onc.1205294
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发表时间：
2002-03-28
期刊：
影响因子：
8
通讯作者：
Rimokh, R
中科院分区：
文献类型：
--
作者：
Bartholin, L;Maguer-Satta, V;Rimokh, R
激活素等转化生长因子β家族成员的信号转导受到可溶性结合蛋白的严格调控。卵泡抑素以高亲和力与激活素A结合，阻止激活素与自身受体结合，从而阻断其信号转导。我们先前在一例携带t(11；19)(q13；p13)易位的B细胞白血病中发现了FLRG基因。我们和其他人已经证明，与卵泡抑素高度同源的FlrG可能通过与激活素结合而参与激活素功能的调节。在这项研究中，我们发现，与卵泡抑素一样，FlrG蛋白抑制了激活素A的信号转导，并阻断了激活素A诱导的对HepG2细胞的生长抑制。我们最近发现，TGFbeta诱导的Flrg的表达是通过Smad蛋白的作用在转录水平上发生的。在这里，我们表明，激活素A增加Flrg和卵泡抑素在mRNA和蛋白质水平。我们发现Smad蛋白参与了激活素A诱导的FlrG和Folistatin的转录激活。最后，我们证明了Flrg蛋白调节其自身激活素诱导的表达。总之，激活素A可诱导FlrG和Follistatin的表达。这一观察结合FlRG和Folistatin对激活素信号的拮抗作用，表明这两种蛋白参与了调节激活素功能的负反馈回路。
Signaling of TGFbeta family members such as activin is tightly regulated by soluble binding proteins. Follistatin binds to activin A with high affinity, and prevents activin binding to its own receptors, thereby blocking its signaling. We previously identified FLRG gene from a B-cell leukemia carrying a t(11;19)(q13;p13) translocation. We and others have already shown that FLRG, which is highly homologous to follistatin, may be involved in the regulation of the activin function through its binding to activin. In this study, we found that, like follistatin, FLRG protein inhibited activin A signaling as demonstrated by the use of a transcriptional reporter assay, and blocked the activin A-induced growth inhibition of HepG2 cells. We have recently shown that the TGFbeta-induced expression of FLRG occurs at a transcriptional level through the action of Smad proteins. Here we show that activin A increases FLRG and follistatin at both the mRNA and protein levels. We found that Smad proteins are involved in the activin A-induced transcription activation of FLRG and follistatin. Finally we demonstrate that FLRG protein regulates its own activin-induced expression. In conclusion, activin A induces FLRG and follistatin expression. This observation, in conjunction with the antagonistic effect of FLRG and follistatin on activin signaling, indicates that these two proteins participate in a negative feedback loop which regulates the activin function.