TGFbeta/BMP inhibits the bone marrow transformation capability of Hoxa9 by repressing its DNA-binding ability.
TGFbeta/BMP inhibits the bone marrow transformation capability of Hoxa9 by repressing its DNA-binding ability.
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TGFbeta/BMP 通过抑制 Hoxa9 的 DNA 结合能力来抑制 Hoxa9 的骨髓转化能力。
DOI：
10.1038/sj.emboj.7601037
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Cao,Xu
中科院分区：
文献类型：
--
作者：
Wang,Ning;Kim,Hyung-Gyoong;Cotta,ClaudiuV;Wan,Mei;Tang,Yi;Klug,ChristopherA;Cao,Xu
同源异型盒（Hox）基因突变及其表达改变通常与人类白血病有关。在这里，我们报告了转化生长因子β（TGFβ）/骨形态发生蛋白（BMP）通过TGFβ/BMP信号通路中常见的Smad（Co-Smad）Smad 4抑制Hoxa 9和Nup 98-Hoxa 9（在人急性髓性白血病（AML）中鉴定的Hoxa 9嵌合融合形式）的骨髓转化能力。Smad 4直接与Hoxa 9的同源结构域相互作用，并阻断Nup 98-Hoxa 9结合DNA的能力，从而抑制其调节下游基因转录的能力。作图数据显示，Smad 4的氨基末端介导这种相互作用，并且Smad 4的Hoxa 9相互作用结构域的过表达足以抑制由Nup 98-Hoxa 9诱导的原代骨髓细胞的增强的连续再铺板能力。这些研究建立了TGFβ/BMP调节造血的新机制，并表明Hox DNA结合活性的修饰可能作为涉及Hox失调的白血病的新治疗干预。
Homeobox (Hox) gene mutations and their altered expressions are frequently linked to human leukemia. Here, we report that transforming growth factor β (TGFβ)/bone morphogenetic protein (BMP) inhibits the bone marrow transformation capability of Hoxa9 and Nup98‐Hoxa9, the chimeric fusion form of Hoxa9 identified in human acute myeloid leukemia (AML), through Smad4, the common Smad (Co‐Smad) in the TGFβ/BMP signaling pathway. Smad4 interacts directly with the homeodomain of Hoxa9 and blocks the ability of Nup98‐Hoxa9 to bind DNA, thereby suppressing its ability to regulate downstream gene transcription. Mapping data revealed that the amino‐terminus of Smad4 mediates this interaction and overexpression of the Hoxa9 interaction domain of Smad4 was sufficient to inhibit the enhanced serial replating ability of primary bone marrow cells induced by Nup98‐Hoxa9. These studies establish a novel mechanism by which TGFβ/BMP regulates hematopoiesis and suggest that modification of Hox DNA‐binding activity may serve as a novel therapeutic intervention for those leukemias that involve deregulation ofHox.