Control of tumorigenesis by the Scribble/Dlg/Lgl polarity module

Cell Cycle and Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
Oncogene (Impact Factor: 8.46). 12/2008; 27(55):6888-907. DOI: 10.1038/onc.2008.341
Source: PubMed


The neoplastic tumour suppressors, Scribble, Dlg and Lgl, originally discovered in the vinegar fly Drosophila melanogaster, are currently being actively studied for their potential role in mammalian tumourigenesis. In Drosophila, these tumour suppressors function in a common genetic pathway to regulate apicobasal cell polarity and also play important roles in the control of cell proliferation, survival, differentiation and in cell migration/invasion. The precise mechanism by which Scribble, Dlg and Lgl function is not clear; however, they have been implicated in the regulation of signalling pathways, vesicle trafficking and in the Myosin II-actin cytoskeleton. We review the evidence for the involvement of Scribble, Dlg, and Lgl in cancer, and how the various functions ascribed to these tumour suppressors in Drosophila and mammalian systems may impact on the process of tumourigenesis.

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    • "lgl was also identified as a dominant suppressor of a weak cyclin E mutant (Brumby et al., 2004). These results raised the possibility that Lgl directly regulates the cell cycle regulatory machinery, in addition to regulating cell polarity (Humbert et al., 2008). Collectively, the mechanism by which Lgl regulates cell proliferation still remains unclear. "
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    ABSTRACT: Lethal giant larvae (Lgl) is an evolutionarily conserved tumor suppressor, whose loss of function causes disrupted epithelial architecture with enhanced cell proliferation and defects in cell polarity. A role for Lgl in the establishment and maintenance of cell polarity, via suppression of the PAR-aPKC polarity complex, is established; however, the mechanism by which Lgl regulates cell proliferation remains not fully understood. Here we show that depletion of Lgl1 and Lgl2 in MDCK epithelial cells results in overproliferation, and overproduction of Lgl2 causes G1 arrest. We also show that Lgl associates with the VprBP-DDB1 complex independently of the PAR-aPKC complex and prevents the VprBP-DDB1 subunits from binding to Cul4A, a central component of the CRL4 [VprBP] ubiquitin E3 ligase complex implicated in G1 to S phase progression. Consistently, depletion of VprBP or Cul4 rescues the overproliferation of Lgl-depleted cells. In addition, the affinity between Lgl2 and the VprBP-DDB1 complex increases at high cell density. Further, aPKC-mediated phosphorylation of Lgl2 negatively regulates the interaction between Lgl2 and VprBP-DDB1 complex. These results suggest a mechanism protecting overproliferation of epithelial cells where Lgl play a critical role to inhibit formation of the CRL4 [VprBP] complex resulting in G1 arrest. © 2015 by The American Society for Cell Biology.
    Molecular biology of the cell 05/2015; 26(13). DOI:10.1091/mbc.E14-10-1462 · 4.47 Impact Factor
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    • "DLG1 is a component of the SCRIB-LGL-DLG complex, and it functions to maintain the basal polarity of epithelial cells 32-34. Another interesting function of DLG1 is that it participates in cell division. "
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    ABSTRACT: Failure in establishment and maintenance of epithelial cell polarity contributes to tumorigenesis. Loss of expression and function of cell polarity proteins is directly related to epithelial cell polarity maintenance. The polarity protein discs large homolog 5 (DLG5) belongs to a family of molecular scaffolding proteins called Membrane Associated Guanylate Kinases (MAGUKs). As the other family members, DLG5 contains the multi-PDZ, SH3 and GUK domains. DLG5 has evolved in the same manner as DLG1 and ZO1, two well-studied MAGUKs proteins. Just like DLG1 and ZO1, DLG5 plays a role in cell migration, cell adhesion, precursor cell division, cell proliferation, epithelial cell polarity maintenance, and transmission of extracellular signals to the membrane and cytoskeleton. Since the roles of DLG5 in inflammatory bowel disease (IBD) and Crohn's disease (CD) have been reviewed, here, our review focuses on the roles of DLG5 in epithelial cell polarity maintenance and cancer development.
    International journal of biological sciences 05/2014; 10(5):543-546. DOI:10.7150/ijbs.8888 · 4.51 Impact Factor
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    • "Homozygous loss-of-function mutations of any of these genes are sufficient to disrupt epithelial architecture and lead to neoplastic transformation of mitotic tissues. Many studies have focused on tissue autonomous roles of the scrib group in tumorigenesis (Bilder et al., 2000; Bilder and Perrimon, 2000; Brumby and Richardson, 2003; Doggett et al., 2011; Dow et al., 2003; Froldi et al., 2008; Humbert et al., 2008; Wu et al., 2010). However, little is known about the effects that a growing tumor has on the physiology of the peripheral tissues. "
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    ABSTRACT: High tumor burden is associated with increased levels of circulating inflammatory cytokines that influence the pathophysiology of the tumor and its environment. The cellular and molecular events mediating the organismal response to a growing tumor are poorly understood. Here, we report a bidirectional crosstalk between epithelial tumors and the fat body-a peripheral immune tissue-in Drosophila. Tumors trigger a systemic immune response through activation of Eiger/TNF signaling, which leads to Toll pathway upregulation in adipocytes. Reciprocally, Toll elicits a non-tissue-autonomous program in adipocytes, which drives tumor cell death. Hemocytes play a critical role in this system by producing the ligands Spätzle and Eiger, which are required for Toll activation in the fat body and tumor cell death. Altogether, our results provide a paradigm for a long-range tumor suppression function of adipocytes in Drosophila, which may represent an evolutionarily conserved mechanism in the organismal response to solid tumors.
    Cell Reports 02/2014; 6(5). DOI:10.1016/j.celrep.2014.01.039 · 8.36 Impact Factor
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