Frameshift mutation of UVRAG, an autophagy-related gene, in gastric carcinomas with microsatellite instability. Hum Pathol
Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea. Human pathology
(Impact Factor: 2.77).
08/2008; 39(7):1059-63. DOI: 10.1016/j.humpath.2007.11.013
Alteration of autophagy is involved in tumor development. Beclin1, an important regulator of autophagy, acts as a tumor suppressor. Ultraviolet (UV) radiation resistance-associated gene (UVRAG) binds with Beclin1 and induces autophagy. There is a polyadenine tract in UVRAG gene (A10 in exon 8) that is a target for frameshift mutations in colorectal carcinomas with microsatellite instability (MSI). Functionally, colon cancer cells with the frameshift mutation of UVRAG show reduced autophagy formation and increased tumorigenicity. The aim of this study was to determine whether the frameshift mutations of UVRAG are also present in gastric carcinomas with MSI. For this, we analyzed human UVRAG exon 8 in 45 gastric carcinomas with MSI and 92 gastric carcinomas without MSI by a single-strand conformation polymorphism analysis. Overall, we detected 3 frameshift mutations of UVRAG in the polyadenine tract (3/45; 6.7%), and all of them were found in MSH-high (H) subtypes (3/32; 9.4%). The 3 mutations consisted of 2 c.708_709delA and 1 c.709delA which would result in premature stops of the UVRAG protein synthesis. The present data indicate that frameshift mutations in the polyadenine tract in UVRAG gene are present in gastric carcinomas as well and suggest that the affected gastric cancer cells with the mutations may have a reduced autophagy activity.
Available from: June-Yong Lee
- "Indeed, centrosome aberrations are considered as a major contributing factor to CIN in cancer cells (Bornens, 2002; Fukasawa, 2007). UV-irradiation-resistance-associated gene (UVRAG) maps to a tumor susceptibility locus on human chromosome 11q13 that is frequently implicated in common human cancers, including breast, colorectal, and gastric cancers (Bekri et al., 1997; Goi et al., 2003; Ionov et al., 2004; Kim et al., 2008; Perelman et al., 1997). We and others have previously shown that UVRAG associates with Beclin1 and activates PI(3) kinase class III (PI(3)KC3) kinase in autophagy (Liang et al., 2006; Matsunaga et al., 2009; Takahashi et al., 2007b; Zhong et al., 2009). "
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ABSTRACT: Autophagy defects have recently been associated with chromosomal instability, a hallmark of human cancer. However, the functional specificity and mechanism of action of autophagy-related factors in genome stability remain elusive. Here we report that UVRAG, an autophagic tumor suppressor, plays a dual role in chromosomal stability, surprisingly independent of autophagy. We establish that UVRAG promotes DNA double-strand-break repair by directly binding and activating DNA-PK in nonhomologous end joining. Disruption of UVRAG increases genetic instability and sensitivity of cells to irradiation. Furthermore, UVRAG was also found to be localized at centrosomes and physically associated with CEP63, an integral component of centrosomes. Disruption of the association of UVRAG with centrosomes causes centrosome instability and aneuploidy. UVRAG thus represents an autophagy-related molecular factor that also has a convergent role in patrolling both the structural integrity and proper segregation of chromosomes, which may confer autophagy-independent tumor suppressor activity.
Available from: Suzie Chen
- "A missense mutation was also identified in UVRAG , a putative tumor suppressor that complements the ultraviolet sensitivity of xeroderma pigmentosum group C cells and also has a role in autophagy ( Kim et al . , 2008 ) . In addition , an 8 - to 12 - fold increase in copy number on chromosome 3p which contains four com - plete genes : RARB , TOP2B , NGLY1 , and KS ( OXSM ) and a four - to sixfold increase on chromosome 15 containing MKRN3 and NDN genes were noted . It is important to point out that this was the first instance that these amplified can"
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ABSTRACT: Genomic variation is a trend observed in various human diseases including cancer. Genetic studies have set out to understand how and why these variations result in cancer, why some populations are predisposed to the disease, and also how genetics affect drug responses. The melanoma incidence has been increasing at an alarming rate worldwide. The burden posed by melanoma has made it a necessity to understand the fundamental signaling pathways involved in this deadly disease. Signaling cascades such as MAPK and PI3K/AKT have been shown to be crucial in the regulation of processes that are commonly dysregulated during cancer development such as aberrant proliferation, loss of cell cycle control, impaired apoptosis and altered drug metabolism. Understanding how these and other oncogenic pathways are regulated has been integral in our challenge to develop potent anti-melanoma drugs. With advances in technology and especially in next generation sequencing, we have been able to explore melanoma genomes and exomes leading to the identification of previously unknown genes with functions in melanomagenesis such as GRIN2A and PREX2. The therapeutic potential of these novel candidate genes is actively being pursued with some presenting as druggable targets while others serve as indicators of therapeutic responses. In addition, the analysis of the mutational signatures of melanoma tumors continues to cement the causative role of UV exposure in melanoma pathogenesis. It has become distinctly clear that melanomas from sun exposed skin areas have distinct mutational signatures including C to T transitions indicative of UV-induced damage. It is thus necessary to continue spreading awareness on how to decrease the risk factors of developing the disease while at the same time working for a cure. Given the large amount of information gained from these sequencing studies, it is likely that in the future, treatment of melanoma will follow a highly personalized route that takes into accou
Available from: cshperspectives.cshlp.org
- "Consistently, ectopic overexpression of BECN1 in colon cancer cell lines with low expression of this gene results in growth inhibition (Koneri et al. 2007). Subsequent to these studies, mutations in other autophagy-related genes including Atg2B, Atg5, Atg9B, Atg12, and UVRAG, have been documented in gastric and colorectal cancers (Kim et al. 2008; Kang et al. 2009). "
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ABSTRACT: (Macro)autophagy is a cellular membrane trafficking process that serves to deliver cytoplasmic constituents to lysosomes for degradation. At basal levels, it is critical for maintaining cytoplasmic as well as genomic integrity and is therefore key to maintaining cellular homeostasis. Autophagy is also highly adaptable and can be modified to digest specific cargoes to bring about selective effects in response to numerous forms of intracellular and extracellular stress. It is not a surprise, therefore, that autophagy has a fundamental role in cancer and that perturbations in autophagy can contribute to malignant disease. We review here the roles of autophagy in various aspects of tumor suppression including the response of cells to nutrient and hypoxic stress, the control of programmed cell death, and the connection to tumor-associated immune responses.
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