This Drosophila model of epithelial cancer makes use of the fly polarity gene scrib and the fly tumor necrosis factor (TNF) family gene egr. Classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\scrib. RNAi-targeting constructs, alleles caused by insertional mutagenesis, and loss-of-function mutations resulting from imprecise excision of TE insertions have been generated for Dmel\egr.
Loss of apical-basal polarity is an early event in the development of epithelial cancers; genes of the Scribble polarity complex have been used extensively in Drosophila models of epithelial cancer (see FBhh0000586). The fly gene scrib is orthologous to two genes in human, SCRIB and LRRC1. Somatic scrib(-) clones induced in developing eye imaginal discs in larvae are observed to have abnormal morphology and show increased proliferation; however, a mechanism to eliminate such clones appears to come into play, since very little scrib(-) tissue is eventually observed in the adult eye. (See the human disease model report 'cancer, epithelial, SCRIB-related' FBhh0000587).
Tumor necrosis factor (TNF) proteins are transmembrane proteins that can be released from the cell membrane by extracellular proteolytic cleavage; they can act via both autocrine and paracrine signaling. This is a large gene family in human; in Drosophila there is a single TNF family gene, eiger (egr). Animals homozygous for the loss-of-function mutation of egr1 are viable and fertile, with minor feeding and immune response phenotypes. Using the scrib model, egr has been found to play a significant role in tumorigenesis in that system. In contrast to the result in wild-type egr animals, somatic scrib(-) clones induced in eye or wing imaginal discs of egr1 homozygous larvae grow aggressively and develop into tumors; the animals typically die in the pupal stage. Additional experiments suggest that egr signaling originates within the scrib(-) clones and acts in an autocrine fashion.
Comparable experiments using animals with RNAi-mediated knockdown of the Drosophila TNF receptor gene grnd give similar results: the elimination of scrib(-) tumors is not observed in animals with reduced levels of grnd.
Multiple physical and genetic interactions have been described for both Dmel\egr and Dmel\scrib; see below and in the respective gene reports.
[updated Nov. 2018 by FlyBase; FBrf0222196]
The SCRIB gene encodes a scaffold protein involved in cell polarization processes; it is involved in tumor suppression pathways (Gene Cards, SCRIB; 2017.08.01).
The tumor necrosis factor (TNF) superfamily is a protein superfamily of type II transmembrane proteins containing TNF homology domain and forming trimers. Members of this superfamily can be released from the cell membrane by extracellular proteolytic cleavage. TNF proteins are expressed predominantly by immune cells and regulate diverse cell functions, including regulation of immune response and inflammation, but also proliferation, differentiation, apoptosis and embryogenesis. The superfamily contains 19 members that bind to 29 members of TNF receptor superfamily. [https://en.wikipedia.org/wiki/Tumor_necrosis_factor_superfamily] This protein family is also called the TNF ligand family.
TNF proteins can act via both autocrine and paracrine signaling (Caldwell et al., 2014; pubmed:25274725).
HGNC currently lists 18 genes in the Tumor Necrosis Factor Superfamily (https://www.genenames.org/data/genegroup/#!/group/781)
SCRIB encodes a cytoplasmic multi-modular scaffold protein targeted to epithelial adherens junctions and neuronal presynaptic compartments. SCRIB and its orthologs in vertebrates and invertebrates participate in the process of cell polarization (summary by Nola et al., 2008; pubmed:18716323). [from MIM:607733; 2018.11.16]
Sole TNF family gene in Drosophila (1 Drosophila to many human); Dmel\egr is most closely related to human EDA, TNFSF13, and TNFSF13B.
Ortholog of human SCRIB and LRRC1 (1 Drosophila to 2 human); Dmel\scrib shares 33% identity and 45% similarity with the human SCRIB gene. The human LRRC1 gene encodes a much smaller protein, corresponding to the amino end of SCRIB and Dmel\scrib; it shares 57% identity and 73% similarity with Dmel\scrib within that extent.
None of the TNF receptor genes in human has been identified as orthologous to grnd.
