Human Disease Model Report: cancer, epithelial, SCRIB-related
Human Disease Model Report: cancer, epithelial, SCRIB-related
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 originally isolated as a tumor suppressor gene (in flies); there are two orthologous genes in human, SCRIB and LRRC1. The mammalian SCRIB gene has also been characterized as a tumor suppressor. Classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\scrib.
Loss of apical-basal polarity is an early event in the development of epithelial cancers. See human diseases model reports 'cancer, epithelial, Scribble-complex-related' (FBhh0000586), 'cancer, epithelial, RAS-SCRIB-related' (FBhh0000585), and 'cancer, epithelial, NOTCH-SCRIB-related' (FBhh0000679).
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. Many physical and genetic interactions for Dmel\scrib have been described; see below and in the gene report for scrib.
To create a context that more accurately emulates the clonal development of tumors, somatic clones have been used. 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. Based on effects of mutations that modulate JNK signaling, it is postulated that the elimination of scrib(-) cells is mediated, at least in part, via the JNK signaling pathway.
This system has been used to characterize gene combinations leading to tumorigenesis (see Related Diseases section, below).
[updated Jul.2019 by FlyBase; FBrf0222196]
SCRIB is 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 cell polarization (summary by Nola et al., 2008; pubmed:18716323). [from OMIM:607733; 2017.08.01]
The SCRIB gene encodes a scaffold protein involved in cell polarization processes; it is involved in tumor suppression pathways. [from Gene Cards, SCRIB; 2017.08.01]
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.
