PubMed:14583476 JSONTXT

{"project":"PubmedHPO","denotations":[{"id":"T1","span":{"begin":163,"end":178},"obj":"HP_0012125"},{"id":"T2","span":{"begin":172,"end":178},"obj":"HP_0002664"},{"id":"T3","span":{"begin":681,"end":696},"obj":"HP_0012125"},{"id":"T4","span":{"begin":690,"end":696},"obj":"HP_0002664"},{"id":"T5","span":{"begin":1219,"end":1234},"obj":"HP_0012125"},{"id":"T6","span":{"begin":1228,"end":1234},"obj":"HP_0002664"},{"id":"T7","span":{"begin":1573,"end":1588},"obj":"HP_0012125"},{"id":"T8","span":{"begin":1582,"end":1588},"obj":"HP_0002664"},{"id":"T9","span":{"begin":1680,"end":1685},"obj":"HP_0002664"}],"text":"Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2',5'-oligoadenylates.\nThe 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."}

{"project":"DisGeNET5_variant_disease","denotations":[{"id":"14583476-9#21#26#geners486907","span":{"begin":1474,"end":1479},"obj":"geners486907"},{"id":"14583476-9#120#135#diseaseC0376358","span":{"begin":1573,"end":1588},"obj":"diseaseC0376358"},{"id":"14583476-9#120#135#diseaseC0600139","span":{"begin":1573,"end":1588},"obj":"diseaseC0600139"}],"relations":[{"id":"21#26#geners486907120#135#diseaseC0376358","pred":"associated_with","subj":"14583476-9#21#26#geners486907","obj":"14583476-9#120#135#diseaseC0376358"},{"id":"21#26#geners486907120#135#diseaseC0600139","pred":"associated_with","subj":"14583476-9#21#26#geners486907","obj":"14583476-9#120#135#diseaseC0600139"}],"text":"Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2',5'-oligoadenylates.\nThe 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."}

{"project":"DisGeNET5_gene_disease","denotations":[{"id":"14583476-0#11#18#gene6041","span":{"begin":11,"end":18},"obj":"gene6041"},{"id":"14583476-0#45#60#diseaseC0376358","span":{"begin":45,"end":60},"obj":"diseaseC0376358"},{"id":"14583476-0#45#60#diseaseC0600139","span":{"begin":45,"end":60},"obj":"diseaseC0600139"},{"id":"14583476-1#177#180#gene3439","span":{"begin":285,"end":288},"obj":"gene3439"},{"id":"14583476-1#177#180#gene3447","span":{"begin":285,"end":288},"obj":"gene3447"},{"id":"14583476-1#4#10#gene6041","span":{"begin":112,"end":118},"obj":"gene6041"},{"id":"14583476-1#44#70#diseaseC2931456","span":{"begin":152,"end":178},"obj":"diseaseC2931456"}],"relations":[{"id":"11#18#gene604145#60#diseaseC0376358","pred":"associated_with","subj":"14583476-0#11#18#gene6041","obj":"14583476-0#45#60#diseaseC0376358"},{"id":"11#18#gene604145#60#diseaseC0600139","pred":"associated_with","subj":"14583476-0#11#18#gene6041","obj":"14583476-0#45#60#diseaseC0600139"},{"id":"177#180#gene343944#70#diseaseC2931456","pred":"associated_with","subj":"14583476-1#177#180#gene3439","obj":"14583476-1#44#70#diseaseC2931456"},{"id":"177#180#gene344744#70#diseaseC2931456","pred":"associated_with","subj":"14583476-1#177#180#gene3447","obj":"14583476-1#44#70#diseaseC2931456"},{"id":"4#10#gene604144#70#diseaseC2931456","pred":"associated_with","subj":"14583476-1#4#10#gene6041","obj":"14583476-1#44#70#diseaseC2931456"}],"text":"Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2',5'-oligoadenylates.\nThe 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."}

{"project":"DisGeNET","denotations":[{"id":"T0","span":{"begin":11,"end":18},"obj":"gene:6041"},{"id":"T1","span":{"begin":45,"end":60},"obj":"disease:C0376358"},{"id":"T2","span":{"begin":11,"end":18},"obj":"gene:6041"},{"id":"T3","span":{"begin":45,"end":60},"obj":"disease:C0600139"}],"relations":[{"id":"R1","pred":"associated_with","subj":"T0","obj":"T1"},{"id":"R2","pred":"associated_with","subj":"T2","obj":"T3"}],"namespaces":[{"prefix":"gene","uri":"http://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"disease","uri":"http://purl.bioontology.org/ontology/MEDLINEPLUS/"}],"text":"Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2',5'-oligoadenylates.\nThe 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."}