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
Source: PubMed


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.

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    • "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.
    Developmental Cell 04/2012; 22(5):1001-16. DOI:10.1016/j.devcel.2011.12.027 · 9.71 Impact Factor
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    • "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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    Frontiers in Genetics 01/2012; 3:330. DOI:10.3389/fgene.2012.00330
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    • "UV irradiation Resistance-Associated Gene (UVRAG), a Becn1 interacting protein that positively regulates autophagy, is allelically deleted in human colon carcinoma (Liang et al., 2006) (Liang et al., 2007a). Moreover, frameshift mutations in the polyadenine tract of the UVRAG gene are present in gastric carcinomas; gastric cancer cells harboring these mutations exhibit decreased autophagy (Kim et al., 2008). In addition, mice lacking Bif 1, which interacts with Becn1 via UVRAG, exhibit significantly higher rate of spontaneous tumors (Takahashi et al., 2007); furthermore, reduced Bif1 expression is observed in gastric carcinoma, which correlates with decreased autophagy (Lee et al., 2006). "
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    ABSTRACT: Autophagy is an evolutionarily conserved lysosomal degradation process that is crucial for adaptation to stress as well as in cellular homeostasis. In cancer, our current understanding has uncovered multifaceted roles for autophagy in tumor initiation and progression. Although genetic evidence corroborates a critical role for autophagy as a tumor suppressor mechanism, autophagy can also promote the survival and fitness of advanced tumors subject to stress, which has important implications during breast cancer progression and metastasis. Here, I discuss the mechanisms and the evidence underlying these diverse roles for autophagy in cancer and speculate on specific circumstances in which autophagy can be most effectively targeted for breast cancer treatment.
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