Drosophila As a Model System for Molecular Analysis of Tumorigenesis

• Published in: Environmental health perspectives 1991-06, Vol.93, p.63-71
• Main Authors: Mechler, Bernard M., Strand, Dennis, Kalmes, Andreas, Merz, Reinhard, Schmidt, Martina, Török, Istvan
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation; Cell Division; Cell growth; Disease Models, Animal; Drosophila; Drosophila melanogaster - embryology; Drosophila melanogaster - genetics; Embryo, Nonmammalian - pathology; Embryonic and Fetal Development; Embryonic cells; Gene Expression Regulation, Neoplastic; Genes, Lethal; Genes, Recessive; Genetic mutation; Germ cells; GTP-Binding Proteins - genetics; Imaginal discs; Insect Hormones - genetics; Insect Hormones - physiology; Insect larvae; Larva; Larval development; Membrane Proteins - genetics; Membrane Proteins - physiology; Neoplasia; Neoplasms, Experimental - genetics; Organ Specificity; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - physiology; Proto-Oncogenes; Repetitive Sequences, Nucleic Acid; Signal Transduction; Tumor Suppressor Genes; Tumors
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/ehp.919363

In Drosophila, homozygous mutations in a series of genes can cause the appearance of tissue-specific tumors. These tumors occur either during embryonic or larval development. The majority of the identified genes give rise to larval tumors that affect either the presumptive adult optic centers of the brain, the imaginal discs, the hematopoietic organs, or the germ cells. These genes act as recessive determinants of neoplasia and have been designated as tumor-suppressor genes. They are normally required for the regulation of cell proliferation and cell differentiation during development. Among these genes, the lethal(2)giant larvae (l(2)gl) has been best studied. Homozygous mutations in l(2)gl produce malignant tumors in the brain hemispheres and the imaginal discs. The l(2)gl gene has been cloned, introduced back into the genome of l(2)gl-deficient animals, and shown to restore normal development. The nucleotide sequence of the l(2)gl gene has been determined, as well as the sequence of its transcripts. Anti-l(2)gl antibodies recognize a protein of about 130 kDa that corresponds to the major product of l(2)gl transcripts. Analysis of the spatial distribution of l(2)gl transcripts and proteins revealed a first phase of intensive expression during embryogenesis and a second weaker phase during the larval to pupal transition period. As revealed by mosaic experiments, the critical period of l(2)gl expression for preventing tumorigenesis takes place during early embryogenesis. During this period, the l(2)gl protein is ubiquitously expressed in all cells and tissues, while during late embryogenesis expression becomes gradually restricted to the midgut epithelium and the axon projections of the ventral nervous system that show no phenotypic alteration in the mutant animals. Biochemical studies revealed that the l(2)gl protein can be metabolically labeled with phosphate and is associated with the cytoplasmic face of the plasma membrane. Sequence comparison has further shown that the l(2)gl proteins contain reiterated sequence motifs that are conserved in G proteins. These data present compelling evidence to implicate l(2)gl in a signal transduction process that ultimately controls cell proliferation and differentiation.