Küssel P, Frasch M
Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, New York 10029, USA.
J Cell Biol. 1995 Jun;129(6):1491-507. doi: 10.1083/jcb.129.6.1491.
We describe the dynamic intracellular localization of Drosophila Pendulin and its role in the control of cell proliferation. Pendulin is a new member of a superfamily of proteins which contains Armadillo (Arm) repeats and displays extensive sequence similarities with the Srp1 protein from yeast, with RAG-1 interacting proteins from humans, and with the importin protein from Xenopus. Almost the entire polypeptide chain of Pendulin is composed of degenerate tandem repeats of approximately 42 amino acids each. A short NH2-terminal domain contains adjacent consensus sequences for nuclear localization and cdc2 kinase phosphorylation. The subcellular distribution of Pendulin is dependent on the phase of cell cycle. During interphase, Pendulin protein is exclusively found in the cytoplasm of embryonic cells. At the transition between G2 and M-phase, Pendulin rapidly translocates into the nuclei where it is distributed throughout the nucleoplasm and the areas around the chromosomes. In the larval CNS, Pendulin is predominantly expressed in the dividing neuroblasts, where it undergoes the same cell cycle-dependent redistribution as in embryos. Pendulin is encoded by the oho31 locus and is expressed both maternally and zygotically. We describe the phenotypes of recessive lethal mutations in the oho31 gene that result in a massive decrease or loss of zygotic Pendulin expression. Hematopoietic cells of mutant larvae overproliferate and form melanotic tumors, suggesting that Pendulin normally acts as a blood cell tumor suppressor. In contrast, growth and proliferation in imaginal tissues are reduced and irregular, resulting in abnormal development of imaginal discs and the CNS of the larvae. This phenotype shows that Pendulin is required for normal growth regulation. Based on the structure of the protein, we propose that Pendulin may serve as an adaptor molecule to form complexes with other proteins. The sequence similarity with importin indicates that Pendulin may play a role in the nuclear import of karyophilic proteins and some of these may be required for the normal transmission and function of proliferative signals in the cells.
我们描述了果蝇Pendulin的动态细胞内定位及其在细胞增殖控制中的作用。Pendulin是一个蛋白质超家族的新成员，该超家族包含犰狳（Arm）重复序列，并且与酵母中的Srp1蛋白、人类的RAG-1相互作用蛋白以及非洲爪蟾的输入蛋白显示出广泛的序列相似性。Pendulin几乎整个多肽链由大约42个氨基酸的简并串联重复序列组成。一个短的NH2末端结构域包含相邻的核定位和cdc2激酶磷酸化共有序列。Pendulin的亚细胞分布取决于细胞周期阶段。在间期，Pendulin蛋白仅存在于胚胎细胞的细胞质中。在G2期和M期之间的转换时，Pendulin迅速转运到细胞核中，分布在整个核质和染色体周围区域。在幼虫中枢神经系统中，Pendulin主要在分裂的神经母细胞中表达，在那里它经历与胚胎中相同的细胞周期依赖性重新分布。Pendulin由oho31基因座编码，在母体和合子中均有表达。我们描述了oho31基因隐性致死突变的表型，这些突变导致合子Pendulin表达大量减少或丧失。突变幼虫的造血细胞过度增殖并形成黑色素瘤，表明Pendulin通常作为血细胞肿瘤抑制因子发挥作用。相反，成虫组织中的生长和增殖减少且不规则，导致幼虫的成虫盘和中枢神经系统发育异常。这种表型表明Pendulin是正常生长调节所必需的。基于该蛋白质的结构，我们提出Pendulin可能作为一种衔接分子与其他蛋白质形成复合物。与输入蛋白的序列相似性表明Pendulin可能在亲核蛋白的核输入中起作用，其中一些可能是细胞中增殖信号正常传递和功能所必需的。
