Bryant P J, Watson K L, Justice R W, Woods D F
Developmental Biology Center, University of California, Irvine 92717.
Dev Suppl. 1993:239-49.
Tumor suppressor genes, whose products are required for the control of cell proliferation, have been identified by their mutant phenotype of tissue overgrowth. Here we describe recent work on the molecular identification of tumor suppressor genes that function in two different cell types of the Drosophila larva: the blood cells, and the undifferentiated epithelial cells of developing imaginal discs. Mutations in the aberrant immune response8 (air8) gene lead to overproduction and precocious differentiation of blood cells. This gene encodes the Drosophila homolog of human ribosomal protein S6. The mutant phenotype is consistent with a role for S6 in the control of cell proliferation, and is compatible with findings from mammalian cells where alterations in S6 expression and phosphorylation are associated with changes in cell proliferation. Mutations in the discs large (dlg) gene cause neoplastic overgrowth of imaginal discs in the larva. The mutant discs show loss of septate junctions and of apical-basal cell polarity, and they also lose the ability to differentiate cuticular structures. The dlg protein product (DlgA) is localized at septate junctions between epithelial cells, and cDNA sequencing indicates that the gene product includes a domain with homology to guanylate kinase (GUK). Two mammalian homologs of this gene have been identified, and one of them (PSD-95/SAP90) encodes a component of synaptic densities in the brain; this protein therefore resembles the DlgA protein in being located in a specialized cell junction that functions in information transfer between cells. Mutations in the fat gene cause hyperplastic imaginal disc overgrowth, in which the overgrowing disc tissue retains its epithelial structure and its ability to differentiate. Some of the excess disc tissue is shed as vesicles suggesting a loss of cell adhesion. In support of this hypothesis, the predicted gene product shows homology to cadherins in its extracellular domain. However, the fat protein is much larger than known cadherins. As in human cancer, somatic loss of the normal alleles of tumor suppressor genes can lead to tumor formation in Drosophila; an example of this is provided by the warts (wts) locus. The wts gene was identified by the dramatic overgrowth of mitotic recombination clones that are homozygous for a wts deletion. In these clones the cuticle intrudes between epithelial cells, suggesting an alteration in cell adhesion. The study of these and other tumor suppressor genes in Drosophila is providing new evidence supporting the critical role of cell interactions and specialized apical junctions in controlling epithelial cell proliferation.
肿瘤抑制基因的产物是控制细胞增殖所必需的，它们通过组织过度生长的突变表型被鉴定出来。在这里，我们描述了最近关于在果蝇幼虫的两种不同细胞类型中发挥作用的肿瘤抑制基因的分子鉴定工作：血细胞和发育中的成虫盘的未分化上皮细胞。异常免疫反应8（air8）基因的突变导致血细胞过度产生和早熟分化。该基因编码人类核糖体蛋白S6的果蝇同源物。突变表型与S6在控制细胞增殖中的作用一致，并且与哺乳动物细胞中的发现相符，在哺乳动物细胞中，S6表达和磷酸化的改变与细胞增殖的变化相关。盘大（dlg）基因的突变导致幼虫成虫盘的肿瘤性过度生长。突变的盘显示隔膜连接和顶-基细胞极性丧失，并且它们也失去了分化表皮结构的能力。dlg蛋白产物（DlgA）定位于上皮细胞之间的隔膜连接处，并且cDNA测序表明该基因产物包括一个与鸟苷酸激酶（GUK）同源的结构域。已经鉴定出该基因的两个哺乳动物同源物，其中一个（PSD-95/SAP90）编码大脑中突触密度的一个成分；因此，这种蛋白质类似于DlgA蛋白，位于在细胞间信息传递中起作用的特化细胞连接处。脂肪（fat）基因的突变导致成虫盘过度增生，其中过度生长的盘组织保留其上皮结构及其分化能力。一些多余的盘组织以囊泡形式脱落，表明细胞粘附丧失。支持这一假设的是，预测的基因产物在其细胞外结构域与钙粘蛋白具有同源性。然而，脂肪蛋白比已知的钙粘蛋白大得多。与人类癌症一样，肿瘤抑制基因正常等位基因的体细胞缺失可导致果蝇肿瘤形成；疣（wts）基因座就是一个例子。wts基因是通过对wts缺失纯合的有丝分裂重组克隆的显著过度生长而鉴定出来的。在这些克隆中，表皮侵入上皮细胞之间，表明细胞粘附发生改变。对果蝇中这些和其他肿瘤抑制基因的研究提供了新的证据，支持细胞相互作用和特化顶端连接在控制上皮细胞增殖中的关键作用。
