Chimeric oncoprotein E2a-Pbx1 induces apoptosis of hematopoietic cells by a p53-independent mechanism that is suppressed by Bcl-2
Chimeric oncoprotein E2a-Pbx1 induces apoptosis of hematopoietic cells by a p53-independent mechanism that is suppressed by Bcl-2
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DOI：
10.1038/sj.onc.1201249
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发表时间：
1997-06-19
期刊：
影响因子：
8
通讯作者：
Cleary, ML
中科院分区：
文献类型：
--
作者：
Smith, KS;Jacobs, Y;Cleary, ML
嵌合癌蛋白 E2a-Pbx1 是 B 细胞前体急性白血病中 t(1;19) 染色体易位后 E2A 和 PBX1 基因融合的结果。实验上，B 细胞祖细胞不耐受 E2a-Pbx1 的组成型表达，这与其他几种细胞类型在体外和体内稳定表达后的转化形成对比。为了进一步研究 E2a-Pbx1 对 B 细胞祖细胞的影响，我们在体外造血前体细胞系中在金属反应元件的控制下条件性表达 E2a-Pbx1，E2a-Pbx1 的诱导表达导致细胞死亡根据细胞凋亡的形态和分子特征，结构功能分析表明，细胞凋亡的诱导不是 E2a 部分的显性负效应，而是需要 Pbx1 的 DNA 结合同源结构域，E2a-Pbx1 诱导的细胞凋亡通过 BCL2 响应性检查点进行，最终导致 PARP 失活，但确实需要 p53。E2a-Pbx1 的组成型表达不会诱导细胞凋亡或继续循环低血清条件下的 Rat-1 成纤维细胞，这些研究表明，E2a-Pbx1 通过需要其嵌合转录特性的机制启动造血前体的程序性细胞死亡，但与其他核癌蛋白不同，它独立于 p53。
The chimeric oncoprotein E2a-Pbx1 results from fusion of the E2A and PBX1 genes following t(1;19) chromosomal translocations in B cell precursor acute leukemias. Experimentally B cell progenitors do not tolerate constitutive expression of E2a-Pbx1 which contrasts with transformation of several other cell types following its stable expression both in vitro and in vivo, To further investigate the effects of E2a-Pbx1 on the B cell progenitors, we conditionally expressed E2a-Pbx1 under control of a metal response element in hematopoietic precursor cell lines in vitro, Inducible expression of E2a-Pbx1 resulted in cell death with the morphologic and molecular features of apoptosis, A structure-function analysis demonstrated that induction of apoptosis was not a dominant-negative effect of the E2a moiety but, rather, required the DNA-binding homeodomain of Pbx1, E2a-Pbx1-induced apoptosis proceeded through a BCL2-responsive checkpoint eventuating in PARP inactivation but did require p53, Constitutive expression of E2a-Pbx1 did not induce apoptosis or continued cycling of Rat-1 fibroblasts in low serum conditions, These studies demonstrate that E2a-Pbx1 initiates programmed cell death of hematopoietic precursers by a mechanism that requires its chimeric transcriptional properties, but, unlike other nuclear oncoproteins, is independent of p53.