Identification and characterization of the ARP1 gene, a target for the human acute leukemia ALL1 gene
Identification and characterization of the ARP1 gene, a target for the human acute leukemia ALL1 gene
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DOI：
10.1073/pnas.95.8.4573
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发表时间：
1998-04-14
影响因子：
11.1
通讯作者：
Croce, CM
中科院分区：
文献类型：
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作者：
Arakawa, H;Nakamura, T;Croce, CM
ALL 1是三胸果蝇的人类同源物，直接参与与11 q23异常相关的人类急性白血病。利用差异显示技术，我们分离出一个在All 1双基因敲除小鼠胚胎干细胞中表达下调的基因。该基因被命名为ARP 1（也称为RIEG、Pxt 2或Otlx 2），是含有与几个同源异型盒基因共享的短基序的同源异型基因家族的成员。使用细菌合成的All 1多肽包含AT-钩基序，我们确定了一个0.5 kb的ARP 1 DNA片段，优先结合到多肽。在该DNA中，约100 bp的区域被多肽保护，不被ExoIII和DNase I消化。对9.5-10.5天的早期小鼠胚胎进行的整体原位杂交表明Arp 1表达与All 1表达在空间上重叠的复杂模式。尽管ARP 1基因在骨髓细胞中强烈表达，但在6个具有11 q23易位的白血病细胞系中未检测到转录本。这些结果表明，ARP 1是上调的All 1蛋白，可能通过直接与上游的DNA序列的前者的相互作用。结果也与由11 q23异常引起的ALL 1嵌合蛋白以显性负性方式起作用的建议一致。
ALL1, the human homologue of Drosophila trithorax, is directly involved in human acute leukemias associated with abnormalities at 11q23. Using the differential display method, we isolated a gene that is down-regulated in All1 double knockout mouse embryonic stem (ES) cells. The gene, designated ARP1 (also termed RIEG, Pxt2, or Otlx2), is a member of a family of homeotic genes containing a short motif shared with several homeobox genes. Using a bacterially synthesized All1 polypeptide encompassing the AT-hook motifs, we identified a 0.5-kb ARP1 DNA fragment that preferentially bound to the polypeptide. Within this DNA, a region of approximate to 100 bp was protected by the polypeptide from digestion with ExoIII and DNase I. Whole-mount in situ hybridization to early mouse embryos of 9.5-10.5 days indicated a complex pattern of Arp1 expression spatially overlapping with the expression of All1. Although the ARP1 gene is expressed strongly in bone marrow cells, no transcripts were detected in six leukemia cell lines with 11q23 translocations. These results suggest that ARP1 is up-regulated by the All1 protein, possibly through direct interaction with an upstream DNA sequence of the former. The results are also consistent with the suggestion that ALL1 chimeric proteins resulting from 11q23 abnormalities act in a dominant negative fashion.