Watson K L, Justice R W, Bryant P J
Developmental Biology Center, University of California, Irvine 92717.
J Cell Sci Suppl. 1994;18:19-33. doi: 10.1242/jcs.1994.supplement_18.4.
In Drosophila, over 50 genes have been identified in which loss-of-function mutations lead to excess cell proliferation in the embryo, in the central nervous system, imaginal discs or hematopoietic organs of the larva, or in the adult gonads. Twenty-two of these genes have been cloned and characterized at the molecular level, and nine of them show clear homology to mammalian genes. Most of these mammalian genes had not been previously implicated in cell proliferation control. Overgrowth in some of the mutants involves conversion to a cell type that, in normal development, shows more cell proliferation than the original cell type. Thus the neurogenic mutants, including Notch, show conversion of epidermal cells to neuroblasts, leading to the 'neurogenic' phenotype of excess nervous tissue. The ovarian tumor mutants show conversion of the female germ line to a cell type resembling the male germ line, which undergoes more proliferation than the female germ line. Mutations of the fat locus cause hyperplastic overgrowth of imaginal discs, in which the epithelial structure is largely intact. The predicted fat protein product is a giant relative of cadherins, supporting indications from human cancer that cadherins play an important role in tumor suppression. Mutations in the lethal(2)giant larvae and lethal(1)discs large genes cause neoplastic overgrowth of imaginal discs as well as the larval brain. The dlg gene encodes a membrane-associated guanylate kinase homolog that is localized at septate junctions between epithelial cells. This protein is a member of a family of homologs that also includes two proteins found at mammalian tight junctions (ZO-1 and ZO-2) and a protein found at mammalian synaptic junctions (PSD-95/SAP90). Genes in which mutations cause blood cell overproduction include aberrant immune response-8, which encodes the RpS6 ribosomal protein and hopscotch, which encodes a putative non-receptor protein tyrosine kinase. The gene products identified by ovarian tumor mutants do not show clear amino acid sequence homology to known proteins. Drosophila provides an opportunity to rapidly identify and characterize tumor suppressor genes, many of which have mammalian homologs that might also be involved in cell proliferation control and tumor suppression.
在果蝇中，已鉴定出50多个基因，其功能丧失突变会导致胚胎、中枢神经系统、幼虫的成虫盘或造血器官，或成年性腺中细胞过度增殖。其中22个基因已被克隆并在分子水平上进行了表征，其中9个与哺乳动物基因具有明显的同源性。这些哺乳动物基因中的大多数以前并未涉及细胞增殖控制。一些突变体中的过度生长涉及转变为一种细胞类型，在正常发育中，这种细胞类型比原始细胞类型表现出更多的细胞增殖。因此，包括Notch在内的神经源性突变体表现出表皮细胞向神经母细胞的转变，导致神经组织过多的“神经源性”表型。卵巢肿瘤突变体表现出雌性生殖系转变为类似于雄性生殖系的细胞类型，后者比雌性生殖系经历更多的增殖。脂肪基因座的突变导致成虫盘的增生性过度生长，其中上皮结构基本完整。预测的脂肪蛋白产物是钙黏蛋白的一个巨大相关物，支持了人类癌症的迹象，即钙黏蛋白在肿瘤抑制中起重要作用。致死（2）巨幼虫和致死（1）盘大基因的突变导致成虫盘以及幼虫大脑的肿瘤性过度生长。dlg基因编码一种膜相关鸟苷酸激酶同源物，定位于上皮细胞之间的分隔连接。该蛋白是一个同源物家族的成员，该家族还包括在哺乳动物紧密连接中发现的两种蛋白（ZO-1和ZO-2）以及在哺乳动物突触连接中发现的一种蛋白（PSD-95/SAP90）。突变导致血细胞过度产生的基因包括异常免疫反应-8，其编码RpS6核糖体蛋白，以及跳房子，其编码一种假定的非受体蛋白酪氨酸激酶。卵巢肿瘤突变体鉴定出的基因产物与已知蛋白没有明显的氨基酸序列同源性。果蝇提供了一个快速鉴定和表征肿瘤抑制基因的机会，其中许多基因具有哺乳动物同源物，这些同源物也可能参与细胞增殖控制和肿瘤抑制。
