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首页> 外文期刊>Molecular and Cellular Biology >The Hox cooperativity motif of the chimeric oncoprotein E2a-Pbx1 is necessary and sufficient for oncogenesis.
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The Hox cooperativity motif of the chimeric oncoprotein E2a-Pbx1 is necessary and sufficient for oncogenesis.

机译：嵌合癌蛋白E2a-Pbx1的Hox协同基序对于肿瘤发生是必要和充分的。

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E2a-Pbx1 chimeric oncoproteins result from fusion of the E2A and PBX1 genes at the sites of t(1;19) chromosomal translocations in a subset acute lymphoblastic leukemias. Experimentally, E2a-Pbx1 transforms a variety of cell types, including fibroblasts, myeloid progenitors, and lymphoblasts. Structure-function studies have shown that contributions from both E2a and Pbx1 are necessary for oncogenesis, but the Pbx1 homeodomain is dispensable and the required portion of Pbx1 has not been delineated. In this study, we used deletional and site-directed mutagenesis to identify portions of Pbx1 necessary for oncogenic and transcriptional activities of E2a-Pbx1. These studies defined a motif (named the Hox cooperativity motif [HCM]) carboxy terminal to the Pbx homeodomain that is required for cooperative DNA binding, cellular transcriptional activity, and the oncogenic potential of E2a-Pbx1. The HCM is highly conserved throughout the Pbx/exd subfamily of divergent homeodomain proteins and functions in DNA-binding assays as a potential contact site for Hox dimerization. E2a-Pbx1 proteins with interstitial deletion or single-point mutations in the HCM could neither activate transcription in cellular assays nor transform NIH 3T3 cells. An E2a-Pbx1 mutant containing 50 amino acids of Pbx1b spanning the HCM but lacking the homeodomain was capable of inducing fibroblast transformation. Thus, the HCM is a necessary and sufficient contribution of Pbx1 for oncogenesis induced by E2a-Pbx1 and accounts for its homeodomain-independent transforming properties. Since subtle alterations of the Pbx HCM result in complete abrogation of transforming activity whereas the homeodomain is entirely dispensable, we conclude that interactions mediated by the HCM are more important for transformation by E2a-Pbx1 than interactions with cognate Pbx DNA sites.
机译：E2a-Pbx1嵌合癌蛋白是由亚型急性淋巴细胞白血病中t（1; 19）染色体易位的E2A和PBX1基因融合产生的。通过实验，E2a-Pbx1可以转化多种细胞类型，包括成纤维细胞，骨髓祖细胞和成淋巴细胞。结构功能研究表明，E2a和Pbx1的贡献对于肿瘤发生都是必需的，但是Pbx1同源结构域是可有可无的，并且Pbx1的必需部分尚未阐明。在这项研究中，我们使用了缺失和定点诱变来鉴定Pbx1的某些部分，这些部分对于E2a-Pbx1的致癌和转录活性是必需的。这些研究为Pbx同源域的羧基末端定义了一个基序（称为Hox协同基序[HCM]），这是合作DNA结合，细胞转录活性和E2a-Pbx1致癌潜力所必需的。在不同的同源域蛋白的Pbx / exd亚家族中，HCM高度保守，并且在DNA结合测定中作为Hox二聚化的潜在接触位点起作用。在HCM中具有间隙缺失或单点突变的E2a-Pbx1蛋白既不能激活细胞测定中的转录也不能转化NIH 3T3细胞。 E2a-Pbx1突变体包含跨越HCM的Pbx1b的50个氨基酸，但缺少同源结构域，能够诱导成纤维细胞转化。因此，HCM是Pbx1对E2a-Pbx1诱导的肿瘤发生的必要和充分的贡献，并说明了其与Homeodomain无关的转化特性。由于Pbx HCM的细微变化导致转化活性的完全废除，而同源结构域则完全是可有可无的，因此我们得出结论，由HCM介导的相互作用对E2a-Pbx1的转化比与同源Pbx DNA位点的相互作用更重要。

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