TRANSFORMATION PROPERTIES OF THE E2A-PBX1 CHIMERIC ONCOPROTEIN - FUSION WITH E2A IS ESSENTIAL, BUT THE PBX1 HOMEODOMAIN IS DISPENSABLE
TRANSFORMATION PROPERTIES OF THE E2A-PBX1 CHIMERIC ONCOPROTEIN - FUSION WITH E2A IS ESSENTIAL, BUT THE PBX1 HOMEODOMAIN IS DISPENSABLE
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DOI：
10.1128/mcb.14.12.8304
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发表时间：
1994-12-01
影响因子：
5.3
通讯作者：
CLEARY, ML
中科院分区：
文献类型：
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作者：
MONICA, K;LEBRUN, DP;CLEARY, ML
t（1; 19）急性淋巴细胞白血病中的染色体易位产生嵌合E2 a-Pbx 1癌蛋白，其可作为DNA结合转录激活剂。对E2 a-Pbx 1功能结构域的结构分析表明，E2 a和Pbx 1的部分对于NIH 3 T3细胞的转化和含有PBX 1共有结合位点的合成报告基因的转录激活是必不可少的。野生型或实验截短的Pbx 1蛋白的过表达不足以转化，与它们不能激活转录一致。当与E2 a融合时，Pbx相关蛋白Pbx 2和Pbx 3也具有转化能力，表明这种高度相似的同源结构域蛋白亚家族的所有已知成员都具有潜在的致癌潜力。E2 a对嵌合体的致癌贡献定位于反式激活蛾AD 1和AD 2，因为它们的突变显著损害了转化。无论是同源结构域或Pbx 1氨基酸侧翼这个区域可以介导转化融合E2 a。然而，同源结构域不是转化所必需的，因为缺乏同源结构域的突变体E2 a-Pbx 1蛋白（E2 a-Pbx（Delta HD））有效地转化成纤维细胞，并在转基因小鼠中诱导恶性淋巴瘤。因此，由嵌合癌蛋白E2 a-Pbx 1介导的转化完全依赖于从E2 a获得的蛾，但Pbx 1同源结构域是可选的。后一项发现表明，E2 a-Pbx 1可能与细胞蛋白相互作用，即使在没有同源结构域-DNA相互作用的情况下，也可以帮助或介导负责肿瘤发生的基因表达的改变。
The t(1;19) chromosomal translocation in acute lymphoblastic leukemias creates chimeric E2a-Pbx1 oncoproteins that can act as DNA-binding activators of transcription. A structural analysis of the functional domains of E2a-Pbx1 showed that portions of both E2a and Pbx1 were essential for transformation of NIH 3T3 cells and transcriptional activation of synthetic reporter genes containing PBX1 consensus binding sites. Hyperexpression of wild-type or experimentally truncated Pbx1 proteins was insufficient for transformation, consistent with their inability to activate transcription. When fused with E2a, the Pbx-related proteins Pbx2 and Pbx3 were also transformation competent, demonstrating that all known members of this highly similar subfamily of homeodomain proteins have latent oncogenic potential. The oncogenic contributions of E2a to the chimeras were localized to transactivation moths AD1 and AD2, as their mutation significantly impaired transformation. Either the homeodomain or Pbx1 amino acids flanking this region could mediate transformation when fused to E2a. However, the homeodomain was not essential for transformation, since a mutant E2a-Pbx1 protein (E2a-Pbx(Delta HD)) lacking the homeodomain efficiently transformed fibroblasts and induced malignant lymphomas in transgenic mice. Thus, transformation mediated by the chimeric oncoprotein E2a-Pbx1 is absolutely dependent on moths acquired from E2a but the Pbx1 homeodomain is optional. The latter finding suggests that E2a-Pbx1 may interact with cellular proteins that assist or mediate alterations in gene expression responsible for oncogenesis even in the absence of homeodomain-DNA interactions.