Mutations in the β-propeller domain of the Drosophila brain tumor (brat) protein induce neoplasm in the larval brain
Mutations in the β-propeller domain of the Drosophila brain tumor (brat) protein induce neoplasm in the larval brain
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DOI：
10.1038/sj.onc.1203706
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发表时间：
2000-08-03
期刊：
影响因子：
8
通讯作者：
Lev, Z
中科院分区：
文献类型：
--
作者：
Arama, E;Dickman, D;Lev, Z
果蝇D.黑腹脑肿瘤（brat）基因导致在幼虫脑中产生肿瘤样肿瘤，并在幼虫第三龄和蛹阶段致死。我们从转座子标记的等位基因克隆了brat基因，并鉴定了其基因产物。hr nt编码1037个氨基酸的蛋白质，其具有N-末端B-box 1锌指，随后是B-box 2锌指，卷曲螺旋结构域和C-末端具有六个叶片的β-螺旋桨结构域。已知所有这些基序介导蛋白质-蛋白质相互作用。4个br at等位基因的序列分析显示，它们都在β-螺旋桨结构域突变。该结构域中突变的聚集强烈表明它在Brat的正常功能中具有关键作用，并定义了一种参与肿瘤抑制活性的新蛋白基序。brat基因在胚胎中枢和外周神经系统包括胚胎脑中表达。在三龄幼虫中，在包括脑和腹神经节的幼虫中枢神经系统中，在两个腺体-环腺和唾液腺中，以及在前肠的部分-胃盲肠和前胃中检测到br nt表达。第二个brat样基因被发现在D，黑腹，同源物被确定在线虫，小鼠，大鼠和人类。大量研究表明，Brat可能通过分泌/转运介导的过程调控细胞增殖和分化。
Inactivation of both alleles of the fruit fly D. melanogaster brain tumor (brat) gene results in the production of a tumor-like neoplasm in the larval brain, and lethality in the Larval third instar and pupal stages. We cloned the brat gene from a transposon-tagged allele and identified its gene product. hr nt encodes for an 1037 amino acid protein with an N-terminal B-box1 zinc finger followed ba a B-box2 zinc finger, a coiled-coil domain, and a C-terminal beta-propeller domain with six blades. All these motifs are known to mediate protein-protein interactions. Sequence analysis of four br at alleles revealed that all of them are mutated at the beta-propeller domain. The clustering of mutations in this domain strongly suggests that it has a crucial role in the normal function of Brat, and defines a novel protein motif involved in tumor suppression activity. The brat gene is expressed in the embryonic central and peripheral nervous systems including the embryonic brain. In third instar larva br nt expression was detected in the Larval central nervous sa stem including the brain and the ventral ganglion, in two glands - the ring gland and the salivary gland, and in parts of the foregut - the gastric caecae and the proventriculus. A second brat-like gene was found in D, melanogaster, and homologs were identified in the nematode, mouse, rat, and human. Accumulated data suggests that Brat may regulate proliferation and differentiation by secretion/transport mediated processes.