Liu F, Hata A, Baker J C, Doody J, Cárcamo J, Harland R M, Massagué J
Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
Nature. 1996 Jun 13;381(6583):620-3. doi: 10.1038/381620a0.
The TGF-beta/activin/BMP cytokine family signals through serine/threonine kinase receptors, but how the receptors transduce the signal is unknown. The Mad (Mothers against decapentaplegic) gene from Drosophila and the related Sma genes from Caenorhabditis elegans have been genetically implicated in signalling by members of the bone-morphogenetic-protein (BMP) subfamily. We have cloned Smad1, a human homologue of Mad and Sma. Microinjection of Smad1 messenger RNA into Xenopus embryo animal caps mimics the mesoderm-ventralizing effects of BMP4. Smad1 moves into the nucleus in response to BMP4. Smad1 has transcriptional activity when fused to a heterologous DNA-binding domain, and this activity is increased by BMP4 acting through BMP-receptor types I and II. The transactivating activity resides in the conserved carboxy-terminal domain of Smad1 and is disrupted by a nonsense mutation that corresponds to null mutations found in Mad and in the related gene DPC4, a candidate tumour-suppressor gene in human pancreatic cancer. Additionally, we show that DPC4 contains a transcriptional activation domain. The results suggests that the Smad proteins are a new class of transcription factors that mediate responses to the TGF-beta family.
转化生长因子-β/激活素/骨形态发生蛋白（BMP）细胞因子家族通过丝氨酸/苏氨酸激酶受体发出信号，但受体如何转导信号尚不清楚。果蝇的Mad（抗五体不全的母亲）基因和秀丽隐杆线虫的相关Sma基因在遗传上与骨形态发生蛋白（BMP）亚家族成员的信号传导有关。我们克隆了Smad1，它是Mad和Sma的人类同源物。将Smad1信使RNA显微注射到非洲爪蟾胚胎动物帽中可模拟BMP4的中胚层腹侧化作用。Smad1会响应BMP4进入细胞核。当与异源DNA结合结构域融合时，Smad1具有转录活性，并且通过I型和II型BMP受体起作用的BMP4会增强这种活性。反式激活活性存在于Smad1保守的羧基末端结构域中，并被一个无义突变破坏，该无义突变与在Mad和相关基因DPC4（人类胰腺癌中的候选肿瘤抑制基因）中发现的无效突变相对应。此外，我们表明DPC4含有一个转录激活结构域。结果表明，Smad蛋白是一类新的转录因子，可介导对转化生长因子-β家族的反应。
