Tumor suppressor genes of Drosophila are developmental genes which, in the homozygously mutated state, induce in one step malignant or benign neoplastic transformation of specific cell types. They act early in development and by this set the stage for cell specific differentiation of imaginal discs, adult optic neuroblasts, blood and gonial cells. The structure, expression and possible function of the following four tumor suppressor genes are discussed: tumorous imaginal disc, lethal (3) malignant brain tumor, lethal (3) malignant blood neoplasm-1 and benign (2) gonial cell neoplasm.

Of the 28 presently known Drosophila tumor suppressor genes we present the status of the functional analysis of the following three genes: (a) lethal(3)malignant brain tumor [1(3)mbt], which by homology belongs to the Pc-G gene family and may be involved in the stable silencing of specific developmental genes by changing the chromatin structure, and thus establishing and maintaining the differentiatied state; (b) lethal (3)malignant blood neoplasm-l [1(3)mbn-1], for whose function only vague predictions can be made; c) benign(2) gonial cell neoplasm [b(2)gcn], which may function as a splice factor. Each Drosophila tumor suppressor gene transforms in the homozygously mutated state either one or two specific cell-types in a single step, and is thus the primary cause for tumorigenesis. For one of the genes a putative human homologue has been found.

Six Drosophila melanogaster tumor suppressor genes causing malignant or benign tumors in specific cell types are described. The wild-type alleles of these genes are instrumental in the differentiation of particular cell types. In the homozygous state, recessive mutations in the genes interrupt the differentiation of the cells and thus cause their uncontrolled, autonomous, lethal proliferation. The tumors show all major characteristics of malignant and benign neoplastic growth. Genomic sequences of four of the genes have been identified and are currently being characterized.

Tumor suppressor genes act as recessive determinants of cancer. These genes contribute to the normal phenotype and are required for regulating cell growth and differentiation during development. Inactivation of tumor suppressor genes leads to an unrestricted pattern of growth in specific cell types. In Drosophila, a series of genes have been identified that cause tissue-specific tumors after mutation. 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 tumors in the brain and the imaginal discs. Genomic DNA from the l(2)gl locus has been cloned, introduced back into the genome of l(2)gl-deficient animals, and shown to reinstate normal development. The nucleotide sequence of the l(2)gl gene has been determined, as well as the sequences of two classes of transcripts. Analysis 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 revealed that l(2)gl gene loss can cause three distinct phenotypes: neoplastic transformation, abnormal differentiation, and normal development. These phenotypes depend upon the extent of gene activity in the stem cells prior to the formation of l(2)gl- clones. These analyses indicate that the critical period for the establishment of tumorigenesis occurs during early embryogenesis at a time when the l(2)gl expression is most intense in all cells.

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.