This model of epithelial cancer uses the Drosophila Scribble polarity complex gene scrib 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, SCRIB-related' (FBhh0000587) and 'cancer, multiple, Hippo signaling pathway' (FBhh0000764).
When activated yki and RNAi directed against scrib are co-expressed in wing discs, large multilayered invasive tumors are formed that degrade the basement membrane. Larvae appeared bloated with overgrown wing discs, enter an extended larval life, and die during the pupal stage. The role of JNK signaling has been investigated in this system and compared to the scrib-Ras85DV12 cancer model system (FBhh0000585).
The Drosophila scrib gene is a cell polarity regulator and neoplastic tumor suppressor; there are two orthologous genes in human, SCRIB and LRRC1. The mammalian SCRIB gene has also been characterized as a tumor suppressor. Dmel\scrib is well characterized genetically: classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. A tagged wild-type transgene of human Hsap\SCRIB has been introduced into flies; partial heterologous rescue (functional complementation) of homozygous Dmel\scrib loss-of-function phenotypes is observed.
Animals homozygous for loss-of-function mutations of Dmel\scrib typically die during the larval stage; imaginal discs exhibit morphology defects, such as increase in size (due to increased cell numbers) and disruption of monolayered epithelial organization.
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.
[updated Aug. 2021 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; 2021.08.03).
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; 2021.08.03]
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 LRRC1.
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.
Moderate-scoring ortholog of human YAP1 and WWTR1 (1 Drosophila to 2 human). Dmel\yki shares 31% identity and 45% similarity with YAP1; it shares 25% identity and 34% similarity with WWTR1.
