Woods D F, Bryant P J
Developmental Biology Center, University of California, Irvine 92717-2275, USA.
Princess Takamatsu Symp. 1994;24:1-13.
Several studies in Drosophila have revealed the existence of loss-of-function mutations that lead to overproliferation of epithelial tissues. The molecular analysis of these tumor suppressor genes has provided important clues in the search for signalling mechanisms controlling growth. We discuss here two genes that act to control epithelial cell proliferation. Mutations in the fat locus cause hyperplastic imaginal disc overgrowth, in which the imaginal disc cells retain their epithelial structure, junctional complexes, and ability to differentiate. However, mutations in fat also cause defective cell-cell adhesion, as indicated by the separation of epithelial vesicles from the epithelial sheet in the mutant tissue. The fat gene encodes a giant relative of cadherins, providing the first evidence that this class of junction-associated molecules can act to regulate growth. Loss of the discs large (dlg) gene product results in neoplastic overgrowth of imaginal discs, causes the epithelial cells to lose apical/basal polarity, and prevents them from differentiating. The gene encodes a protein made up of a series of peptide motifs, including an SH3 and a potential enzymatic domain, a region homologous to guanylate kinases. The presence of these domains suggests a role for Dlg in guanine nucleotide-mediated signal transduction. The Dlg protein is restricted to a specific apical junctional complex in Drosophila epithelial cells, the septate junction. It is the first identified member of a new family of junction-associated proteins that includes ZO-1 and ZO-2, major components of vertebrate tight junctions. These results suggest that junctional contacts could play previously unrecognized roles in regulating the growth of epithelial tissues and that ZO-1 and/or ZO-2 may act as tumor suppressor proteins in humans.
果蝇的多项研究揭示了功能丧失性突变的存在，这些突变会导致上皮组织过度增殖。对这些肿瘤抑制基因的分子分析为寻找控制生长的信号传导机制提供了重要线索。我们在此讨论两个控制上皮细胞增殖的基因。脂肪基因座的突变会导致成虫盘过度增生，其中成虫盘细胞保留其上皮结构、连接复合体和分化能力。然而，脂肪基因的突变也会导致细胞间黏附缺陷，这在突变组织中上皮小泡与上皮层分离中得到体现。脂肪基因编码一种钙黏蛋白的巨大相关蛋白，这首次证明了这类与连接相关的分子可以调节生长。盘大（dlg）基因产物的缺失会导致成虫盘肿瘤性过度生长，使上皮细胞失去顶端/基底极性，并阻止它们分化。该基因编码一种由一系列肽基序组成的蛋白质，包括一个SH3和一个潜在的酶结构域，一个与鸟苷酸激酶同源的区域。这些结构域的存在表明Dlg在鸟嘌呤核苷酸介导的信号转导中起作用。Dlg蛋白局限于果蝇上皮细胞中一个特定的顶端连接复合体，即分隔连接。它是一个新的与连接相关的蛋白质家族中第一个被鉴定的成员，该家族包括ZO-1和ZO-2，它们是脊椎动物紧密连接的主要成分。这些结果表明，连接接触可能在调节上皮组织生长中发挥以前未被认识的作用，并且ZO-1和/或ZO-2可能在人类中作为肿瘤抑制蛋白发挥作用。
