Tumor suppressor genes and signal transduction in Drosophila.
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.
Woods
D F
DF
Developmental Biology Center, University of California, Irvine 92717-2275, USA.
Bryant
P J
PJ
D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D016764:Cell Polarity / Q000235:genetics; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000235:genetics*; D004847:Epithelial Cells; D016147:Genes, Tumor Suppressor; D006965:Hyperplasia; D019476:Insect Proteins / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D005810:Multigene Family; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000235:genetics*; D025521:Tumor Suppressor Proteins; D018909:src Homology Domains
D015820:Cadherins; D029721:Drosophila Proteins; D019476:Insect Proteins; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; C070350:dlg1 protein, Drosophila