This report describes Drosophila models of cancer that combine mutations that result in overexpression of the Notch signaling pathway with misexpression of various genes within the PI3K/AKT pathway. Targeted overexpression of the Notch pathway is achieved by driving overexpression of the Notch ligand Delta (Dl); overexpression of Dl in the adult eye results in a mild overgrowth phenotype. In combination with increased expression of Akt, hyperproliferation in observed; in combination with increased expression of Pi3K92E, invasive and metastatic growth is observed. Overexpression of Dl in combination with increased expression of Pten results suppression of overgrowth phenotypes; when combined with knockdown of Pten effected by RNAi, a dramatic increase in hyperproliferation results. These systems have been used to assess the efficacy of antitumorigenic drugs that target inflammatory pathways.
In human, there are 4 genes that encode NOTCH family transmembrane receptor proteins (NOTCH1-NOTCH4); there are 2 genes similar to the Drosophila Notch ligand Delta (DLL1 and DLL4) and 2 genes similar to the Drosophila Notch ligand Serrate (JAG1 and JAG2). For PI3K-AKT signaling pathway genes, Dmel\Pi3K92E is orthologous to human PIK3C kinase catalytic subunit genes; Dmel\ Pten is orthologous to human PTEN phosphatase, a negative regulator of the PI3K/AKT pathway; Dmel\Pdk1 is orthologous to human PDPK1 kinase; and Dmel\Akt is orthologous to human AKT kinase genes.
[updated Dec. 2018 by FlyBase; FBrf0222196]
Moderate- to high-scoring ortholog of human DLL1 and DLL4 (1 Drosophila to 2 human); additional less closely related genes in human. Dmel\Dl shares 39% identity and 51-53% similarity with human DLL1 and DLL4.
Moderate- to high-scoring ortholog of human genes AKT2, AKT3, and AKT1 (1 Drosophila to 3 human). Dmel\Akt shares 60-64% identity and 75-77% similarity with these human genes.
High-scoring ortholog of human PIK3CD and PIK3CB; moderate-scoring ortholog of PIK3CG and PIK3CA (1 Drosophila to 4 human). Dmel\Pi3K92E shares 31-39% identity and 50-58% similarity with the human genes.
High-scoring ortholog of human PTEN (1 Drosophila to 1 human). Dmel\Pten shares 41% identity and 57% similarity with the human gene.