This report describes a Drosophila model of cancer that combines a constitutively activated mutation in the fly gene Notch (N) with gain-of-function mutations in the fly gene Mef2. Dmel\N encodes a transmembrane receptor that plays a key role in intercellular signaling; the fly gene is orthologous to 4 human genes, NOTCH1-NOTCH4. Dmel\Mef2 is a member of the MADS-box family of transcription factors; there are 3 high-scoring orthologs in human, MEF2A, MEF2C, and MEF2D.
None of the human genes has been introduced into flies.
Two gain-of-function insertional mutations of Dmel\Mef2 were isolated in a genetic screen designed to identify enhancers of the eye overgrowth phenotype observed when an constitutively activated allele of N (NICN.UAS) is expressed in the developing eye. Neither Mef2 mutation alone results in an overgrowth phenotype. Combination of a gain-of-function mutation or eye-specific overexpression of Mef2 with expression of activated N results in a severe overproliferation phenotype in the eye disc and subsequently in the eye. At a low frequency, ectopic eye tissue is observed in the thorax or abdomen, suggesting invasive cell behavior. Experiments support the hypothesis that the N-Mef2 overproliferation and invasive phenotypes are effected by activation of JNK signaling.
See also the human disease model report 'cancer, multiple, Notch signaling pathway' (FBhh0000766).
[updated Mar. 2018 by FlyBase; FBrf0222196]
In human, there are 4 known genes encoding the NOTCH family of proteins, a group of receptors involved in the Notch signaling pathway. NOTCH proteins are characterized by N-terminal EGF-like repeats followed by LNR domains which form a complex with ligands to prevent signaling. The Notch signaling pathway is involved in processes related to cell fate specification, differentiation, proliferation, and survival. [Gene Cards, NOTCH1; 2017.12.06]
There are multiple human genes in the MADS box transcription enhancer factor 2 (MEF2) family of proteins. They encode transcriptional activators that binds specifically to the MEF2 element found in many muscle-specific genes and are also involved in the activation of numerous growth factor- and stress-induced genes. [Gene Cards, MEF2A, MEF2C; 2018.03.20]
Moderate- to high-scoring ortholog of human NOTCH1, NOTCH2, NOTCH3, NOTCH4 (1 Drosophila to 4 human). Dmel\N shares 43-44% identity and 56-57% similarity with NOTCH1 and NOTCH2.
Moderate-scoring ortholog of human MEF2A, MEF2C, and MEF2F (1 Drosophila to 3 human); additional more distantly related genes in human. Dmel\Mef2 shares 43% identity and 56% similarity with MEF2A; it shares 32-35% identity and 43-46% similarity with MEF2C and MEF2F.
