This model of epithelial cancer uses the Drosophila Scribble polarity complex gene l(2)gl in combination with a transcriptional co-activator regulated by the Hippo signaling pathway, the Drosophila gene yki. The highly conserved Scribble polarity complex plays a key role in determining cell polarity and cell proliferation in epithelial cells. One of the human gene orthologous to Dmel\yki, YAP1, is known to play a role in the development and progression of multiple cancers. See also 'cancer, epithelial, Scribble-complex-related' (FBhh0000586) and 'cancer, epithelial, RAS-LLGL-related' (FBhh0000588).
In human, there are two genes orthologous to Dmel\l(2)gl, the cytoskeletal proteins LLGL1 and LLGL2. Classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for l(2)gl; an amorphic allele has been created via gene targeting and recombination. A tagged wild-type transgene of human Hsap\LLGL1 has been introduced into flies; partial heterologous rescue (functional complementation) of the homozygous Dmel\l(2)gl lethal phenotype is observed.
Animals homozygous for loss-of-function mutations of Dmel\l(2)gl typically die during the larval stage. Somatic clones that are homozygous for loss-of-function mutations of l(2)gl exhibit a cell polarity defect; mutant cells are eliminated from mosaic epithelia by cell competition. Multiple physical and many genetic interactions for Dmel\l(2)gl have been described; see below and in the gene report for l(2)gl.
In human, there are two genes orthologous to Dmel\yki, YAP1 and WWTR1. Classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for yki; an amorphic allele has been created via gene targeting and recombination. Multiple UAS constructs of the human Hsap\YAP1 gene have been introduced into flies, including wild-type and genes with mutations eliminating phosphorylation sites.
Animals homozygous for an amorphic mutation of Dmel\yki die as late embryos and early first instar larvae. Somatic clones are difficult to recover and are very small, indicating that complete loss of function is virtually cell-lethal. Models of cancer involving Dmel\yki use a constitutively active form or drive overexpression of a wild-type gene. MANY physical and genetic interactions for Dmel\yki have been described; see below and in the gene report for yki.
[updated Aug. 2017 by FlyBase; FBrf0222196]
YAP1 encodes a transcriptional regulator which can act both as a coactivator and a corepressor and is the critical downstream regulatory target in the Hippo signaling pathway; it thus plays a key role development, growth, repair, and homeostasis. YAP1 is known to play a role in the development and progression of multiple cancers. [Gene Cards, YAP1; 2017.08.01]
LLGL1 and LLGL2 encode cortical cytoskeleton proteins found in a complex involved in maintaining cell polarity and epithelial integrity, the Scribble Cell Polarity Complex. This complex plays a role in the initial phase of the establishment of epithelial cell polarity; it is involved in the regulation of mitotic spindle orientation, proliferation, differentiation, and tissue organization of neuroepithelial cells. [Gene Cards, LLGL1, LLGL2; 2017.08.01]
Many to one: 2 human to 1 Drosophila; the second human gene is WWTR1.
Many to one: 2 human to 1 Drosophila; the second human gene is LLGL2.
Many to one: 2 human to 1 Drosophila; the second human gene is LLGL1.