Liu B, Dou C L, Prabhu L, Lai E
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Mol Cell Biol. 1999 Jan;19(1):424-30. doi: 10.1128/MCB.19.1.424.
The mechanisms by which transforming growth factor beta (TGF-beta) and related ligands regulate transcription remain poorly understood. The winged-helix (WH) transcription factor fork head activin signal transducer 1 (FAST-1) was identified as a mediator of activin signaling in Xenopus embryos (X. Chen, M. J. Rubock, and M. Whitman, Nature 383:691-696, 1996). We have cloned a novel WH gene from the mouse which shares many properties with FAST-1. We find that this gene, which we call FAST-2, is able to mediate transcriptional activation by TGF-beta. FAST-2 also interacts directly with Smad2, a cytoplasmic protein which is translocated to the nucleus in response to TGF-beta, and forms a multimeric complex with Smad2 and Smad4 on the activin response element, a high-affinity binding site for FAST-1. Analysis of the sequences of FAST-1 and FAST-2 reveals substantial protein sequence divergence compared to known vertebrate orthologs in the WH family. This suggests that FAST-2 represents a new WH gene related to FAST-1, which functions to mediate TGF-beta signals in mammals. We have also examined the structure of the FAST-2 gene and find that it overlaps with a kinesin motor protein gene. The genes are transcribed in opposite orientations, and their transcripts overlap in the 3' untranslated region.
转化生长因子β（TGF-β）及相关配体调节转录的机制仍知之甚少。翼状螺旋（WH）转录因子叉头激活素信号转导子1（FAST-1）被鉴定为非洲爪蟾胚胎中激活素信号的介质（X. Chen、M. J. Rubock和M. Whitman，《自然》383:691 - 696，1996）。我们从小鼠中克隆了一个与FAST-1具有许多共同特性的新型WH基因。我们发现这个我们称为FAST-2的基因能够介导TGF-β的转录激活。FAST-2还直接与Smad2相互作用，Smad2是一种细胞质蛋白，在TGF-β作用下转位至细胞核，并在激活素反应元件（FAST-1的高亲和力结合位点）上与Smad2和Smad4形成多聚体复合物。对FAST-1和FAST-2序列的分析表明，与WH家族中已知的脊椎动物直系同源物相比，它们的蛋白质序列存在显著差异。这表明FAST-2代表了一个与FAST-1相关的新WH基因，其功能是在哺乳动物中介导TGF-β信号。我们还研究了FAST-2基因的结构，发现它与一个驱动蛋白基因重叠。这两个基因以相反方向转录，它们的转录本在3'非翻译区重叠。
