Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Discs Large (Dlg) protein is known to be involved in the regulation of cellular proliferation and polarity in a variety of tissues. The human homologue DLG1 is thought to be a tumour suppressor, through formation of a complex with the APC (adenomatous polyposis coli) protein, causing negative regulation of the cell cycle. An alternative oncogenic role has also been proposed, in which the PI3-kinase pathway is activated under the influence of the adenovirus E4 ORF1 protein. The differing roles seem to be related to differences in the precise pattern of expression. However, the biochemical pathways involved in regulating DLG1 function during different phases of the cell cycle remain unclear. In this study we show that phosphorylation is a major post-translational modification of the protein and it affects both location and function. DLG1 lies at the cellular junctions in G1, is enriched in the cytoplasm in S phase and locates to the mitotic spindle in M phase. We also show that DLG1 is phosphorylated by both CDK1 and CDK2 on Ser158 and Ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on Ser158 and Ser442 in its putative nuclear functions as a tumour suppressor. In addition, the mutants at these sites demonstrate different half-lives as well as different susceptibilities to ubiquitylation, suggesting a role for these phosphorylation events in controlling DLG1 protein stability. These findings establish phosphorylation events as key regulators of DLG1 localisation and function.
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PMID:CDK phosphorylation of the discs large tumour suppressor controls its localisation and stability. 1906 88

Discs-large (DLG) is a multi-PDZ domain-containing protein that belongs to the family of molecular scaffolding proteins known as membrane guanylate kinases or MAGUKs. DLG is a component of the Scribble polarity complex and genetic analyses of DLG in Drosophila have identified a role for the protein in several key biological processes including the regulation of apico-basal polarity of epithelial cells, as well as other polarity processes such as asymmetric cell division and cell invasion. Disturbance of DLG function leads to uncontrolled epithelial cell proliferation and neoplastic transformation, thereby defining DLG as a potential tumour suppressor. However, whether mammalian homologues of DLG (DLG1, DLG2, DLG3 and DLG4) also possess tumour suppressor functions is not known. In this minireview, we focus on the biological functions of DLG1 in human epithelial cells and on how the function of this MAGUK relates to its intracellular location. We examine some of the evidence that implies that DLG has both tumour suppressor and, paradoxically, oncogenic functions depending upon the precise cellular context.
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PMID:The PDZ protein discs-large (DLG): the 'Jekyll and Hyde' of the epithelial polarity proteins. 2284 45

Human Discs large tumour suppressor (DLG1) participates in regulating cell polarity and proliferation, suggesting an important connection between epithelial organization and cellular growth control. However, it was demonstrated that DLG1 could acquire oncogenic attributes in some specific contexts. In this work, we evaluated the expression of DLG1 and its contribution to the progress of cervical lesions in order to investigate a potential role of this polarity protein in human oncogenic processes. We analyzed cervical biopsies from women with low-grade squamous intraepithelial lesion (LSIL) diagnosis (n=30), for DLG1 expression by immunohistochemistry. These results were correlated with the clinical monitoring of the patients during a 24-month follow-up period. Our data indicate that while all LSIL patients with a DLG1 staining pattern similar to normal tissues are significantly more likely to regress (n=23, Pattern I), all LSIL biopsy specimens showing a diffuse and intense DLG1 staining likely progress to high-grade lesions (n=4, Pattern II). Finally, all persistent LSIL analyzed showed an undetermined DLG1 staining, with a diffuse distribution without a strong intensity (n=3, Pattern III). We found a significant association between the expression pattern of DLG1 and the evolution of the lesion (p<0.00001). This work contributes to the knowledge of DLG1 biological functions, suggesting that its expression may have an important role in the progression of early dysplastic cervical lesions, giving prognostic information.
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PMID:DLG1 polarity protein expression associates with the disease progress of low-grade cervical intraepithelial lesions. 2804 May 5