This Drosophila model of epithelial cancer makes use of the fly gene Alg3, which is an N-glycosyltransferase, specifically a mannosyltransferase. Dmel\Alg3 is orthologous to human ALG3; the human gene is associated with a congenital disorder of glycosylation (MIM:601110). Classical loss-of-function mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\Alg3.
The human ALG3 gene has not been introduced into flies.
Animals that are transheterozygous for Dmel\Alg3 loss-of-function alleles exhibit slowly developing hyperplastic phenotypes in imaginal discs, resulting in a prolonged larval stage, increased body size, greatly enlarged discs, and larval or pupal lethality. In wild-type imaginal discs, mitotic clones that are mutant for Alg3 (LOF) are partially outcompeted compared with wild-type, supporting a mechanism to eliminate such clones. Mitotic clones that carry the activated Ras85DV12 allele, in addition to being mutant for Alg3, appear to overcome that mechanism and exhibit much higher levels of overgrowth than clones carrying either mutation alone (see the disease model report 'cancer, multiple, RAS-related' FBhh0000474).
In Drosophila, Alg3 has been shown to target a membrane-associated TNF receptor (TNFR), Dmel\grnd. In imaginal discs, RNAi-effected knockdown of grnd in portions of Alg3 mutant discs reverts the overgrowth phenotype in that region of the disc. It is postulated that reduced glycosylation of grnd, due to loss-of-function mutations in Dmel\Alg3, results in increased binding of circulating TNF (Dmel\egr); this leads to overactivity of JNK signaling in the affected cells. The roles of Dmel\egr and Dmel\grnd are also addressed in the disease model reports 'cancer, epithelial, TNF-SCRIB-related' (FBhh0000926) and 'cancer, epithelial, TNF-SCRIB-RAS-related' (FBhh0000927).
Genetic interactions of Dmel\Alg3 have been described; see the Alg3 gene report.
[updated Dec. 2018 by FlyBase; FBrf0222196]
High-scoring ortholog of human ALG3 (1 Drosophila to 1 human). Dmel\Alg3 shares 45% identity and 56% similarity with the human gene.
None of the TNF receptor genes in human has been identified as orthologous to grnd.