A model of cancer initiation and progression has been developed using the Drosophila scrib gene in combination with the Drosophila Notch (N) gene. See also the human disease model reports 'cancer, epithelial, SCRIB-related' (FBhh0000587), and 'cancer, epithelial, Scribble-complex-related' (FBhh0000586).
The Scribble polarity complex plays a key role in determining cell polarity and cell proliferation in epithelial cells. The eponymous 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. To create a context that more accurately emulates the clonal development of tumors, somatic clones have been used; somatic clones that are homozygous for loss-of-function mutations of scrib exhibit overgrowth phenotypes. Many physical and genetic interactions for Dmel\scrib have been described; see below and in the gene report for scrib.
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 activate 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.
Expression of scrib loss-of-function alleles in somatic clones in combination with a constitutively active N transgene results in a more extreme overproliferation of the clonal cells than is observed with either modification alone, resulting in dramatic tissue overgrowth.
[updated Dec. 2017 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]
Many to one: 2 human to 1 Drosophila; the second human gene is LRRC1.
Many to one (4 human to 1 Drosophila). The human genes are NOTCH1, NOTCH2, NOTCH3 and NOTCH4.
Many to one (4 human to 1 Drosophila). The human genes are NOTCH1, NOTCH2, NOTCH3 and NOTCH4.
Many to one (4 human to 1 Drosophila). The human genes are NOTCH1, NOTCH2, NOTCH3 and NOTCH4.
Many to one (4 human to 1 Drosophila). The human genes are NOTCH1, NOTCH2, NOTCH3 and NOTCH4.
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- to high-scoring ortholog of human NOTCH1, NOTCH2, NOTCH3 and NOTCH4 (1 Drosophila to 4 human). Dmel\N shares 33-44% identity and 44-57% similarity with the human genes.
