Disease relevance of UVRAG

• UVRAG-mediated activation of the Beclin1-PI(3)KC3 complex promotes autophagy and also suppresses the proliferation and tumorigenicity of human colon cancer cells [1].
• Ascending colon cancer with hepatic metastasis and cholecystolithiasis in a patient with situs inversus totalis without any expression of UVRAG mRNA: report of a case [2].
• On the basis of its consistency and magnitude of cancer cell-specific expression, we propose AMACR as an important new marker of prostate cancer and that its use in combination with p63 staining will form the basis for an improved staining method for the identification of prostate carcinomas [3].
• In a simple assay that can be useful for the diagnosis of prostate cancer on both biopsy and surgical specimens, combined staining for p63 and AMACR resulted in a staining pattern that greatly facilitated the identification of malignant prostate cells [3].
• In addition, p63 was present in virions, resulting in transient, early appearance in newly infected cells [4].

High impact information on UVRAG

• p73 (ref. 1) has high homology with the tumour suppressor p53 (refs 2-4), as well as with p63, a gene implicated in the maintenance of epithelial stem cells [5].
• UVRAG, a tumour suppressor candidate that is monoallelically mutated at high frequency in human colon cancers, associates with the Beclin1-Bcl-2-PI(3)KC3 multiprotein complex, where UVRAG and Beclin1 interdependently induce autophagy [1].
• p63 regulates an adhesion programme and cell survival in epithelial cells [6].
• Apoptosis induced by loss of p63 was rescued by signalling downstream of beta4 integrin [6].
• Knockdown of p63 expression caused downregulation of cell adhesion-associated genes, cell detachment and anoikis in mammary epithelial cells and keratinocytes [6].

Chemical compound and disease context of UVRAG

• Gleevec suppresses p63 expression in head and neck squamous cell carcinoma despite p63 activation by DNA-damaging agents [7].

Biological context of UVRAG

• UVRAG was assigned to human chromosome 11 by Southern hybridization to a somatic cell hybrid panel [8].
• These results identify UVRAG as an essential component of the Beclin1-PI(3)KC3 lipid kinase complex that is an important signalling checkpoint for autophagy and tumour-cell growth [1].
• Conversely, overexpression of the TAp63gamma or deltaNp63alpha isoforms of p63 upregulated cell adhesion molecules, increased cellular adhesion and conferred resistance to anoikis [6].
• p63, a member of the p53 family of transcription factors, plays an important role in epithelial development, regulating both cell cycle and apoptosis [9].
• We further show that the transactivation domain at the NH(2) terminus of p63 represses, whereas the COOH terminus activates hsp70 transcription [10].

Anatomical context of UVRAG

• Our results implicate p63 as a key regulator of cellular adhesion and survival in basal cells of the mammary gland and other stratified epithelial tissues [6].
• Accordingly, p63 protein levels are significantly increased in Itch knockout keratinocytes [9].
• Generation of specific cytotoxic T cells with a fragment of the Epstein-Barr virus-encoded p63/latent membrane protein [11].
• A mAb against a novel 63 kDa membrane protein (p63) was produced that identifies a large tubular network of smooth membranes in the cytoplasm of primate cells [12].
• We have developed monoclonal antibodies to a 63,000-molecular-weight protein (p63) which is the product of the most abundant messenger RNA in Epstein-Barr virus-transformed cells and shown that the protein is associated specifically with plasma membranes [4].

Associations of UVRAG with chemical compounds

• Delineation of the ADULT syndrome phenotype due to arginine 298 mutations of the p63 gene [13].
• No myosin immunoreactivity was seen in the luminal/tumor cells, but p63 pattern of staining in the luminal/tumor cells was quite similar to that of p75NTR [14].
• We used monoclonal antibodies reactive to p63 or TTF-1 to stain 4-microns-thick sections from 30 formalin-fixed, paraffin-embedded lung biopsy and resection specimens and 7 alcohol-fixed, formalin-postfixed, paraffin-embedded cell blocks from lung fine-needle aspirations (FNAs) [15].
• Basal cells were observed on regular hematoxylin and eosin stained slides in 14 cases; in all the cases, basal cells were confirmed by immunohistochemical stains for high molecular weight cytokeratin (n=25) and/or p63 (n=4) [16].
• CONCLUSIONS: Gleevec downregulates p63/DeltaNp63 levels in HNSCC in a dose-dependent manner under both normal and DNA-damaging conditions [7].

Physical interactions of UVRAG

• UVRAG interacts with Beclin 1, leading to activation of autophagy and thereof inhibition of tumorigenesis [17].

Other interactions of UVRAG

• This finding adds a new player to the emerging picture of the autophagy network, under-scoring the importance of the coordinated activity between Bcl-2 and UVRAG in the regulation of Beclin 1-PI3KC3-mediated autophagy and tumor cell control [17].

Analytical, diagnostic and therapeutic context of UVRAG

• The distribution of p63 overlaps with the ER-Golgi intermediate compartment, defined by a previously described 53 kDa marker protein (here termed ERGIC-53), as visualized by confocal laser scanning immunofluorescence microscopy and immunoelectron microscopy [12].
• Newly synthesized p63 was detected at the time cells underwent blast transformation (48 to 72 h postinfection) [4].
• By immunohistochemistry, 7 (100%) out of 7 were positive for p63 and 14 (88%) of 16 were positive for high molecular weight cytokeratin [18].
• Specific activation of p63-selected long-term CD4(+) T cell cultures resulted in a proliferative response, in the production of IL-2 and in the secretion of high levels of tumor necrosis factor as measured by bioassays [19].
• ESCs were isolated from newborn rat epidermis by rapid adhesion to IV collagen and examined by immunofluorescence staining to detect p63 and k14 expression [20].

References