HoxA9-mediated immortalization of myeloid progenitors requires functional interactions with TALE cofactors Pbx and Meis
HoxA9-mediated immortalization of myeloid progenitors requires functional interactions with TALE cofactors Pbx and Meis
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DOI：
10.1038/sj.onc.1203371
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发表时间：
2000-02-03
期刊：
影响因子：
8
通讯作者：
Cleary, ML
中科院分区：
文献类型：
--
作者：
Schnabel, CA;Jacobs, Y;Cleary, ML
特异性Hox基因与白血病转化有关，它们与TALE同源盒基因Pbx和Meis的选择性遗传合作，增强了它们的致癌潜力。然而，这些配位功能背后的分子机制尚未被表征。在这项研究中，我们证明HoxA9需要它的Pbx相互作用基序以及它的氨基末端来增强体外骨髓祖细胞的克隆潜能。我们进一步证明HoxA9在修饰的增强子上与Pbx和meis样蛋白形成功能性三聚体DNA结合复合物。含有HoxA9和TALE同型蛋白的DNA结合复合物显示协同转录活性，并存在于白血病细胞中。然而，三聚体复合体的形成本身并不足以实现hoxa9介导的永生化。相反，结构功能分析表明，HoxA9的结构域是细胞转化所必需的，与三聚体介导的转录激活所需要的结构域是一致的。此外，HoxA9的氨基端提供了必要的转录效应特性，其对髓系转化的要求可以在功能上被VP16激活域取代。这些数据表明，HoxA9和TALE同型蛋白之间的生化相互作用介导造血细胞的细胞转化，它们在高阶DNA结合复合体中的转录活性为它们在白血病发生中的协同作用提供了分子基础。
Specific Hox genes are implicated in leukemic transformation, and their selective genetic collaboration with TALE homeobox genes, Pbx and Meis, accentuates their oncogenic potential. The molecular mechanisms under-lying these coordinate functions, however, have not been characterized. In this study, we demonstrate that HoxA9 requires its Pbx interaction motif as well as its amino terminus to enhance the clonogenic potential of myeloid progenitors in vitro. We further show that HoxA9 forms functional trimeric DNA binding complexes with Pbx and Meis-like proteins on a modified enhancer. DNA binding complexes containing HoxA9 and TALE homeoproteins display cooperative transcriptional activity and are present in leukemic cells. Trimeric complex formation on its own, however, is not sufficient for HoxA9-mediated immortalization. Rather, structure-function analyses demonstrate that domains of HoxA9 which are necessary for cellular transformation are coincident with those required for trimer-mediated transcriptional activation. Furthermore, the amino terminus of HoxA9 provides essential transcriptional effector properties and its requirement for myeloid transformation can be functionally replaced by the VP16 activation domain. These data suggest that biochemical interactions between HoxA9 and TALE homeoproteins mediate cellular transformation in hematopoietic cells, and that their transcriptional activity in higher order DNA binding complexes provides a molecular basis for their collaborative roles in leukemo-genesis.