Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.27.5 (RNase)
 17,967 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The RNASEL gene (2',5'-oligoisoadenylate-synthetase dependent) encodes a ribonuclease that mediates the antiviral and apoptotic activities of interferons. The RNASEL gene maps to the hereditary-prostate-cancer (HPC)-predisposition locus at 1q24-q25 (HPC1) and was recently shown to harbor truncating mutations in two families with linkage to HPC1. Here, we screened for RNASEL germline mutations in 66 Finnish patients with HPC, and we determined the frequency of the changes in the index patients from 116 families with HPC, in 492 patients with unselected prostate cancer (PRCA), in 223 patients with benign prostatic hyperplasia (BPH), and in 566 controls. A truncating mutation, E265X, was found in 5 (4.3%) of the 116 patients from families with HPC. This was significantly higher (odds ratio [OR] =4.56; P=.04) than the frequency of E265X in controls (1.8%). The highest mutation frequency (9.5%) was found in patients from families with four or more affected members. Possible segregation was detected only in a single family. However, the median age at disease onset for E265X carriers was 11 years less than that for noncarriers in the same families. In addition, of the four missense variants found, R462Q showed an association with HPC (OR=1.96; P=.07). None of the variants showed any differences between controls and either patients with BPH or patients with PRCA. We conclude that, although RNASEL mutations do not explain disease segregation in Finnish families with HPC, the variants are enriched in families with HPC that include more than two affected members and may also be associated with the age at disease onset. This suggests a possible modifying role in cancer predisposition. The impact that the RNASEL sequence variants have on PRCA burden at the population level seems small but deserves further study.
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PMID:Germline alterations of the RNASEL gene, a candidate HPC1 gene at 1q25, in patients and families with prostate cancer. 1194 39

The RNASEL gene, a strong candidate for the hereditary prostate cancer 1 allele (HPC1), encodes a single-stranded specific endoribonuclease involved in the antiviral actions of IFNs. RNase L is activated enzymatically after binding to unusual 5'-phosphorylated, 2',5'-linked oligoadenylates (2-5A). Biostable phosphorothioate analogues of 2-5A were synthesized chemically and used to study the effects of naturally occurring mutations and polymorphisms in RNASEL. The 2-5A analogues induced RNase L activity and caused apoptosis in cultures of late-stage, metastatic human prostate cancer cell lines DU145, PC3, and LNCaP. However, DU145 and PC3 cells were more sensitive to 2-5A than LNCaP cells, which are heterozygous for an inactivating deletion mutation in RNase L. The RNase activities of missense variants of human RNase L were compared after expression in a mouse RNase L(-/-) cell line. Several variants (G59S, I97L, I220V, G296V, S322F, Y529C, and D541E) produced similar levels of RNase L activity as wild-type enzyme. In contrast, the R462Q variant, previously implicated in up to 13% of unselected prostate cancer cases, bound 2-5A at wild-type levels but had a 3-fold decrease in RNase activity. The deficiency in RNase L(R462Q) activity was correlated with a reduction in its ability to dimerize into a catalytically active form. Furthermore, RNase L(R462Q) was deficient in causing apoptosis in response to 2-5A consistent with its possible role in prostate cancer development. Our findings support the notion that RNASEL mutations and some variants allow tumor cells to escape a potent apoptotic pathway.
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PMID:Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2',5'-oligoadenylates. 1458 76

RNase-L mediates critical cellular functions including antiviral, pro-apoptotic, and tumor suppressive activities; accordingly, its expression must be tightly regulated. Little is known about the control of RNASEL expression; therefore, we examined the potential regulatory role of a conserved 3'-untranslated region (3'-UTR) in its mRNA. The 3'-UTR mediated a potent decrease in the stability of RNase-L mRNA, and of a chimeric beta-globin-3'-UTR reporter mRNA. AU-rich elements (AREs) are cis-acting regulatory regions that modulate mRNA stability. Eight AREs were identified in the RNase-L 3'-UTR, and deletion analysis identified positive and negative regulatory regions associated with distinct AREs. In particular, AREs 7 and 8 served a strong positive regulatory function. HuR is an ARE-binding protein that stabilizes ARE-containing mRNAs, and a predicted HuR binding site was identified in the region comprising AREs 7 and 8. Co-transfection of HuR and RNase-L enhanced RNase-L expression and mRNA stability in a manner that was dependent on this 3'-UTR region. Immunoprecipitation demonstrated that RNase-L mRNA associates with a HuR containing complex in intact cells. Activation of endogenous HuR by cell stress, or during myoblast differentiation, increased RNase-L expression, suggesting that RNase-L mRNA is a physiologic target for HuR. HuR-dependent regulation of RNase-L enhanced its antiviral activity demonstrating the functional significance of this regulation. These findings identify a novel mechanism of RNase-L regulation mediated by its 3'-UTR.
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PMID:Post-transcriptional regulation of RNase-L expression is mediated by the 3'-untranslated region of its mRNA. 1723 28

Prostate Cancer (CAP), is a complex disease with a multifactorial origin. It is characterized by heterogenous patterns of growth of neoplasic tissue, varying widely in its progression, age of beginning and therapy response. It is considered as the second most common cause of death by cancer in men and, it has been estimated, that one of five, suffers of CAP through the course of his life. The genetic etiology of neoplasic transformation of normal prostate cells is still not known; nevertheless, investigations in epidemiology have demonstrated a strong genetic component in its development, suggesting so much a pattern of mendelian inheritance as the presence of loci of susceptibility throughout the human genome. It has been described a cromosomic location related to the CAP in locus 1q24-25, denominated HPC1, where the gene RNASEL is located, and the seggregation of its alleles has been associated with the development of CAP in numerous familiar groups. The RNASEL gene codifies for a ribonuclease protein that degrades vi-ral and cellular ARN and takes part in the apoptosis. A decrease of the enzymatic activity up to three times in carriers of the G1385A polymorphism of this gene has been reported, and the same has been associated frequently with the development of CAP. Using a variant of the Polymerase Chain Reaction, Allele specific amplification, this investigation had as objective to determine the association between variant G1385A and CAP, in a sample of 103 masculine individuals with and without CAP, pertaining to the population of Maracaibo, Venezuela. An association between these variants and CAP could not be demonstrated.
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PMID:[G138A polymorphism of the RNASEL gene and its association with the development of prostate cancer. Preliminary study]. 1996 Oct 52

The endoribonuclease RNase-L is the terminal component of an interferon-regulated RNA decay pathway known as the 2'-5'-oligoadenylate (2-5A) system, whose established functions include antimicrobial and tumor suppressive activities. RNase-L activity requires binding of the small molecule 2-5A, leading to RNase-L dimerization and cleavage of single-stranded RNA. RNase-L expression is controlled post-transcriptionally by its 3'-untranslated region (3' UTR), which exerts a strong negative effect on RNase-L levels. MicroRNAs (miRNAs) are a class of small noncoding RNAs that repress expression of target genes by binding to regions of complementarity often in the 3' UTR. The miR-29 family acts as a tumor suppressor in several cancers, including acute and chronic myelogenous leukemia (CML), and has many oncogenic targets. We report that the miR-29 family represses RNase-L protein expression across several cell types. Using a luciferase reporter, we showed that miR-29 acts via 4 target sites within the RNASEL 3' UTR. Mutation of all sites is required for abrogation of miR-29 repression. In light of the reported tumor suppressive role of miR-29 in K562 CML cells and miR-29 repression of RNase-L in these cells, we generated K562 cells with stable RNase-L knockdown and demonstrated that loss of RNase-L inhibits proliferation in vitro as well as tumor growth in a xenograft model. Our findings identify a previously unknown miRNA regulator of RNase-L expression and support a novel oncogenic role for RNase-L in CML and potentially other hematopoietic malignancies.
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PMID:Regulation of human RNase-L by the miR-29 family reveals a novel oncogenic role in chronic myelogenous leukemia. 2311 44

The RNASEL gene (2', 5'-oligoisoadenylate synthetase-dependent) encodes a ribonuclease that plays a significant role in the apoptotic and antiviral activities of interferons. Various studies have used polymorphisms in the RNASEL gene to evaluate prostate cancer risk but studies that show an association between RNASEL Arg462Gln (1385G>A, R462Q, rs486907) polymorphism and prostate cancer risk are somewhat inconclusive. To assess the impact of RNASEL Arg462Gln polymorphism on prostate cancer risk, we conducted a meta-analysis of all available studies including 11,522 patients and 10,976 control subjects. The overall results indicated no positive association between the variant and prostate cancer risk. However, in a subgroup analysis by ethnicity, obvious associations were observed in Hispanic Caucasians for allelic contrast (OR = 1.18, 95% CI = 1.00 - 1.39, Pheterogeneity = 0.010), homozygote comparison (OR = 1.50, 95% CI = 1.02 - 2.20, Pheterogeneity = 0.001), and the recessive genetic model (OR = 1.44, 95% CI = 1.01 - 2.05, Pheterogeneity = 0.002) ; and in African descendants for homozygote comparison (OR = 2.59, 95% CI = 1.29 - 5.19, Pheterogeneity = 0.194) and the recessive genetic model (OR = 2.61, 95% CI = 1.30 - 5.23, Pheterogeneity = 0.195). In conclusion, the RNASEL Arg462Gln polymorphism may contribute to the risk of developing prostate cancer in African descendants and Hispanic Caucasians. Further larger and well-designed studies are warranted to evaluate this association in detail.
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PMID:Association of a common genetic variant in RNASEL and prostate cancer susceptibility. 2908 52