Molecular Basis for the Regulation of Cell Fate by the Lethal (2) Giant Larvae Tumour Suppressor Gene of Drosophila Melanogaster

Abstract

Tumour suppressor genes act as recessive determinants of cancer. Their function is required for normal cell growth and differentiation during development. When both alleles of these developmental genes are inactivated, cell growth becomes unrestricted. In Drosophila, a series of genes have been identified which when mutated produce tissue-specific tumours. Of these the lethal(2)giant larvae (l(2)gl) gene is the best studied. Homozygous l(2)gl mutations cause the development of malignant tumours in the brain and the imaginal discs. Genomic DNA from the l(2)gl locus has been cloned, introduced back into l(2)gl mutant animals by P-element-mediated transformation and shown to restore normal development. The nucleotide sequence of the l(2)gl gene (13.1 kb) has been determined, as well as the sequences of the two classes of transcripts. These transcripts encode two polypeptides of 127 kDa and 78 kDa, respectively. Both proteins have been immunologically identified. Analyses of the spatial distribution of both l(2)gl transcripts and proteins revealed that during early embryogenesis the l(2)gl gene is uniformly expressed in all cells and tissues. In late embryos, the l(2)gl expression becomes gradually restricted to tissues presenting no morphological or neoplastic alteration in the mutant animals. Further mosaic experiments pointed out that the critical period for the establishment of tumorigenesis is limited to early embryogenesis at a time when the l(2)gl expression is most intense in all cells.