<i>RNASEL</i> germline variants are associated with pancreatic cancer

Bartsch, Detlef K.; Fendrich, Volker; Slater, Emily P.; Sina-Frey, Mercedes; Rieder, Harald; Greenhalf, William; Chaloupka, Brunhilde; Hahn, Stephan A.; Neoptolemos, John P.; Kress, Ralf

doi:10.1002/ijc.21254

Cited by 39 publications

(27 citation statements)

References 20 publications

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“…Several genetic polymorphisms (involving missense mutations in the RNASEL gene) associated with prostate cancer are shown: M1I [19]; a four-nucleotide deletion at codon 157 [23], a truncating mutation E265X [19,24,25], R400P [25], R462Q [19,24,26] and D541E [26]. In addition, R462Q has also been associated with aggressive tumours in familial pancreatic cancer [27] but also retroviruses such as the HTLV type II. The precise pathogenesis of chronic fatigue syndrome remains unknown, although microbial infections could trigger and perpetuate the disease [34].…”

Section: Xmrv In Chronic Fatigue Syndromementioning

confidence: 96%

Evidence and controversies on the role of XMRV in prostate cancer and chronic fatigue syndrome

Menéndez‐Arias

2010

Reviews in Medical Virology

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The recent discovery of xenotropic murine leukaemia virus-related virus (XMRV) in prostate cancer tissues and in the blood of individuals suffering from chronic fatigue syndrome has attracted considerable interest. However, the relevance and significance of XMRV to human disease remain unclear, since the association has not been confirmed in other studies. XMRV is the first gammaretrovirus to be found in humans. XMRV and murine leukaemia viruses share similar structures and genomic organisation. Human restriction factors such as APOBEC3 or tetherin inhibit XMRV replication. Although XMRV induces low rates of transformation in cell culture, it might be able to induce cancer by low-frequency insertional activation of oncogenes or through the generation of highly active transforming viruses. A preference for regulatory regions of transcriptional active genes has been observed after a genomic-wide analysis of XMRV integration sites. Genes related to carcinogenesis and androgen signalling have been identified in the vicinity of integration sites. The XMRV genome contains a glucocorticoid responsive element, and androgens could modulate viral replication in the prostate. Evidence supporting the involvement of XMRV in chronic fatigue syndrome is still very weak, and needs further confirmation and validation. Currently approved anti-retroviral drugs such as zidovudine, tenofovir and raltegravir are efficient inhibitors of XMRV replication in vitro. These drugs might be useful to treat XMRV infection in humans. The identification of XMRV has potentially serious health implications for the implementation of novel techniques including gene therapy or xenotransplantation, while raising concerns on the need for screening donated blood to prevent transmission through transfusion.

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Section: Xmrv In Chronic Fatigue Syndromementioning

confidence: 96%

Evidence and controversies on the role of XMRV in prostate cancer and chronic fatigue syndrome

Menéndez‐Arias

2010

Reviews in Medical Virology

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“…As prostate cancer occurs in some familial pancreatic families, Bartsch and co-workers evaluated the role of two variants of RNASEL gene: E265X and R462Q in the etiology of pancreatic cancer [141]. That study showed that the RNASEL R462Q variant might be associated with an increased risk for sporadic pancreas cancer and with more aggressive tumors in familial pancreatic cancer.…”

Section: ) Pancreatic Cancer and Colorectal Cancermentioning

confidence: 99%

Diverse functions of RNase L and implications in pathology

Bisbal

Silverman

2007

Biochimie

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The endoribonuclease L (RNase L) is the effector of the 2-5A system, a major enzymatic pathway involved in the molecular mechanism of interferons (IFN). RNase L is a very unusual nuclease with a complex mechanism of regulation. It is a latent enzyme, expressed in nearly every mammalian cell type. Its activation requires its binding to a small oligonucleotide, 2-5A. 2-5A is a series of unique 5′-triphosphorylated oligoadenylates with 2′-5′ phosphodiester bonds. By regulating viral and cellular RNA expression, RNase L plays an important role in the antiviral and antiproliferative activities of IFN and contributes to innate immunity and cell metabolism. The 2-5A/RNase L pathway is implicated in mediating apoptosis in response to viral infections and to several types of external stimuli. Several recent studies have suggested that RNase L could have a role in cancer biology and evidence of a tumor suppressor function of RNase L has emerged from studies on the genetics of hereditary prostate cancer. KeywordsInterferon; RNase L; RNA expression; apoptosis; prostate; virus; cancer I) IntroductionThe endoribonuclease L (RNase L) is the effector of the 2-5A system, a major enzymatic pathway regulated by interferons (IFN) [1] (Figure 1). The 2-5A system is one of the two antiviral pathways induced by IFN and activated by double stranded RNA (dsRNA), the other is mediated by the dsRNA dependent protein kinase (PKR) [2]. RNase L is a very unusual nuclease. It is a latent enzyme, expressed in nearly every mammalian cell type. Its activation requires its binding to a small oligonucleotide, 2-5A ( Figure 1). 2-5A itself is very unusual, consisting of a series of 5′-triphosphorylated oligoadenylates with 2′-5′ phosphodiester bonds in contrast to the 3′-5′ linkages found in RNA and DNA. The initial and essential observation was made by Ian Kerr's group in 1974 reporting an IFN-induced increase in the sensitivity of protein synthesis to inhibition by dsRNA [3]. Peter Lengyel's group observed increased nuclease activity in extracts of interferon treated cells incubated with dsRNA [4,5]. The identification by Ian Kerr's group of the activators of this nuclease, 2-5A [6] and of the enzyme responsible for their synthesis, the 2-5A-synthetase [7][8][9], led to the discovery of the 2-5A pathway. Clemens and Williams directly demonstrated a nuclease, now recognized as RNase Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Figure 2). The N-terminal domain could be considered as the regulatory domain of RNase L. It is composed of eight complete and one partial ankyrin motifs (R1-R9). Two wal...

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“…Promising results were obtained for variants in NAT2 , RNASEL , GSTM1, IL-4, MPO, SOD2, XPC and UGT1A7, the latter possibly interacting with smoking [47][48][49][50][51][52][53] . At the same time, negative results have been reported for mostly non-synonymous coding SNPs in NAT1 , NAT2, GSTM1 , GSTT1 , NAD(P)H , NQO1 , UGT1A7 , UGT1A9 , ARP , SPINK1 , CFTR , CYP1A1 , CYP2D6 , CYP2E1, HFE [47,49,[54][55][56][57][58] .…”

Section: Other Studiesmentioning

confidence: 99%