A model of cancer of epidermal origin has been developed using the Drosophila l(2)gl gene in combination with an activated form of the Drosophila Notch (N) gene. See also the human disease model reports 'cancer, epithelial, LLGL-related' (FBhh0000591), and 'cancer, epithelial, Scribble-complex-related' (FBhh0000586).
l(2)gl encodes a component of the Scribble polarity complex; this complex plays a key role in determining cell polarity and cell proliferation in epithelial cells. In human, there are two genes orthologous to Dmel\l(2)gl, the cytoskeletal proteins LLGL1 and LLGL2. Animals homozygous for loss-of-function mutations of Dmel\l(2)gl typically die during the larval stage and exhibit abnormal overproliferation of tissues, including in the brain, imaginal discs, and hematopoietic organs; cell-polarity defects are observed. Classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\l(2)gl.
The Notch signaling pathway is involved in processes related to cell fate specification, differentiation, proliferation, and survival. In human, there are 4 known genes that encode NOTCH family proteins; there is a single orthologous gene in Drosophila (the founding member of this gene family), Notch or N. In flies, most work relevant to cancer has been done with a constitutively active N transgene; ectopic expression of constitutively active N in somatic clones surrounded by wild-type tissue results in hyperproliferative effects. N is one the most thoroughly studied genes in Drosophila: hundreds of alleles, extensive physical interactions, and an unwieldy number of genetic interactions have been described; see below and in the gene report for N.
In eye discs, RNAi-mediated knockdown of l(2)gl in combination with constitutively active N results in more extreme overproliferation than is observed with either modification alone, resulting in dramatic tissue overgrowth. MMP1 (a reporter for JNK signaling) upregulation and loss of epithelial integrity are observed.
[updated Jun. 2019 by FlyBase; FBrf0222196]