A Hippo signaling pathway gene.
Koyama et al. (1996) isolated cDNA clones from a human brain cDNA library for the human homolog of the murine Llglh
gene that was originally isolated as a homolog of the Drosophila tumor suppressor gene 'lethal(2) giant larvae' (l(2)gl). The
full-length cDNA encodes 1,033 amino acids with 40% identity to the Drosophila l(2)gl amino acid sequence and 86%
identity to the murine homolog. Northern analysis of mRNA revealed that this gene was expressed as a 4.4-kb transcript in a
wide range of tissues; however, more abundant expression occurred in brain and testes.
The human protein Hugl-1 substitutes for Drosophila lethal giant larvae tumour suppressor function in vivo. Grifoni D et al. Drosophila lethal giant larvae: (lgl), discs large (dlg) and scribble (scrib) are tumour suppressor genes acting in a common pathway, whose loss of function leads to disruption of cell polarity and tissue architecture, uncontrolled proliferation and growth of neoplastic lesions. Mammalian homologues of these genes are highly conserved and evidence is emerging concerning their role in cell proliferation control and tumorigenesis in humans. Here we investigate the functional conservation between Drosophila lethal giant larvae and its human homologue Hugl-1(Llgl1). We first show that Hugl-1 is lost in human solid malignancies, supporting its role as a tumour suppressor in humans. Hugl-1 expression in homozygous lgl Drosophila mutants is able to rescue larval lethality; imaginal tissues do not show any neoplastic features, with Dlg and Scrib exhibiting the correct localization; animals undergo a complete metamorphosis and hatch as viable adults. These data demonstrate that Hugl-1 can act as a tumour suppressor in Drosophila and thus is the functional homologue of lgl. Furthermore, our data suggest that the genetic pathway including the tumour suppressors lgl, dlg and scrib may be conserved in mammals, since human scrib and mammalian dlg can also rescue their respective Drosophila mutations. Our results highlight the usefulness of fruit fly as a model system for investigating in vivo the mechanisms linking loss of cell polarity and cell proliferation control in human cancers.
NCBI Summary:
This gene encodes a protein that is similar to a tumor suppressor in Drosophila. The protein is part of a cytoskeletal network and is associated with nonmuscle myosin II heavy chain and a kinase that specifically phosphorylates this protein at serine residues. The gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]
General function
Intracellular signaling cascade, Tumor suppressor
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Cellular localization
Cytoskeleton
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Ovarian function
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Basolateral junctions utilize warts signaling to control epithelial-mesenchymal transition and proliferation crucial for migration and invasion of Drosophila ovarian epithelial cells. Zhao M et al. Fasciclin2 (Fas2) and Discslarge (Dlg) localize to the basolateral junction (BLJ) of Drosophila follicle epithelial cells and inhibit their proliferation and invasion. To identify a BLJ signaling pathway we completed a genomewide screen for mutants that enhance dlg tumorigenesis. We identified two genes that encode known BLJ scaffolding proteins, lethal giant larvae (lgl) and scribble (scrib), and several not previously associated with BLJ function, including warts (wts) and roughened eye (roe), which encode a serine-threonine kinase and a transcription factor, respectively. Like scrib, wts and roe also enhance Fas2 and lgl tumorigenesis. Further, scrib, wts, and roe block border cell migration, and cause noninvasive tumors that resemble dlg partial loss of function, suggesting that the BLJ utilizes Wts signaling to repress EMT and proliferation, but not motility. Apicolateral junction proteins Fat (Ft), Expanded (Ex), and Merlin (Mer) either are not involved in these processes, or have highly spatio-temporally restricted roles, diminishing their significance as upstream inputs to Wts in follicle cells. This is further indicated in that Wts targets, CyclinE and DIAP1, are elevated in Fas2, dlg, lgl, wts, and roe cells, but not Fat, ex, or mer cells. Thus, the BLJ appears to regulate epithelial polarity and dynamics not only as a localized scaffold, but also by communicating signals to the nucleus. Wts may be regulated by distinct junction inputs depending on developmental context.
Expression regulated by
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Ovarian localization
Oocyte, Granulosa
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Baek KH,ET AL 2002 reported molecular cloning and characterization of bovine bgl-1, a novel
family member of WD-40 repeat-containing lethal giant larvae
tumor suppressor genes.
They isolated a bovine homologue bgl-1 of lethal giant larvae (lgl)
tumor suppressor oncogene from bovine brain by RT-PCR using primers designed
based on the conserved sequences for lgl family members. The sequence analysis
showed that the bgl-1 encodes a 1,036 amino acid polypeptide with the molecular
weight of approximately 112 kDa containing a domain characteristic of WD-40
proteins. The amino acid sequence of bgl-1 showed a homology of 98.3 and 87.3%
identity to that of mouse and human, respectively. Northern blot analysis showed that
bgl-1 was highly expressed in brain, ovary and testis, with moderate expression in
liver, uterus, lung and kidney. This suggests that the bgl-1 may play essential roles in
each of these organs. The complementation analysis revealed that the bovine bgl-1
partially restored the Na+ tolerance in the absence of yeast lgl homologue, suggesting
that bgl-1 is a bovine homologue of the lgl family.
Follicle stages
Antral
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Huang JH, et al 2003 reported that murine discslarge-1, discslarge-3, discslarge-4, lethal giant larvae, and scribble are expressed in both overlapping and distinct patterns in oocytes and granulosa cells in maturing follicles. The data suggests that as in Drosophila, these tumor suppressors may cooperate during mammalian folliculogenesis, but also have distinct functions.