Disease relevance of RNASEL

• RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases [1].
• RNASEL germline variants are associated with pancreatic cancer [2].
• We thus mapped the RNASEL transcriptional start site using 5'-rapid amplification of cDNA ends (5'-RACE) and primer extension methods with RNA from human histiocytic lymphoma U937 cells [3].
• Lack of association between RNASEL Arg462Gln variant and the risk of breast cancer [4].
• We reevaluated the role of the RNASEL 471delAAAG Ashkenazi founder mutation in 1,642 Ashkenazi patients with prostate, bladder, breast/ovarian, and colon cancers; Ashkenazi controls; and in non-Ashkenazi prostate cancer patients and controls [5].
• This is the first study that investigates the association of prostate cancer risk with RNASEL variants in Hispanic men [6].

Psychiatry related information on RNASEL

• Because both the 2-5A system and apoptosis can serve as viral defense mechanisms and RNA degradation occurs during both processes, we investigated the potential role of RNase L in apoptosis [7].

High impact information on RNASEL

• There is good evidence that a variety of viruses encode functions that inhibit activation of either ribonuclease L or the Pl/eIF-2 alpha kinase [8].
• Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway might provide opportunities for developing therapies for those with prostate cancer [9].
• RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway and has been suggested to be a candidate tumor suppressor gene [9].
• We found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozyogous individuals compared with family members who were homozygous with respect to the wildtype allele [9].
• Analysis of aligned murine and human 2-5A-dependent RNAse sequences revealed several intriguing features, including similarity to RNAase E, which is implicated in the control of mRNA stability in E. coli [10].

Chemical compound and disease context of RNASEL

• A 2',5'-oligoadenylate (2-5A)-dependent 37-kDa form of RNase L has been reported in extracts of peripheral blood mononuclear cells (PBMC) from individuals with chronic fatigue syndrome (CFS) [11].
• Phosphorothioate/phosphodiester trimer and tetramer 2-5A derivatives revealed differences in the stereodynamics of activation of RNase L and inhibition of HIV-1 replication [12].
• Purine 8-bromination modulates the ribonuclease L binding and activation abilities of 2',5'-oligoadenylates. Possible influence of glycosyl torsion angle [13].

Biological context of RNASEL

• The RNASEL gene on chromosome 1q25 was recently identified as a candidate gene for hereditary prostate cancer (PC) [14].
• We identified a novel founder frameshift mutation in RNASEL, 471delAAAG, in Ashkenazi Jews [15].
• HPC1/RNASEL mediates apoptosis of prostate cancer cells treated with 2',5'-oligoadenylates, topoisomerase I inhibitors, and tumor necrosis factor-related apoptosis-inducing ligand [16].
• The association of mutations in RNASEL with prostate cancer cases further suggests a relationship between innate immunity and tumor suppression [17].
• Exon 2 of the RNASEL gene was directly sequenced in the germline of 36 familial and 75 sporadic pancreatic cancer patients and in 108 controls [2].

Anatomical context of RNASEL

• The known 471delAAAG truncating mutation was found in the RNASEL gene in cell line LNCaP [18].
• An Alternative Spliced RNASEL Variant in Peripheral Blood Leukocytes [19].
• Quantitative RT-PCR measurements of RNA from different PBL cell types separated by fluorescence activated cell sorting (FACS) showed that complete RNASEL mRNA levels were significantly elevated in granulocytes compared with all other PBL cell types, whereas expression was lowest in CD8(+) T cells [19].
• Its expression in reticulocyte extracts antagonizes the 2-5A binding ability and the nuclease activity of endogenous RNase L or the cloned 2DR polypeptide [20].
• We found that a fraction of cellular RNase L and RLI is localized in the mitochondria [21].

Associations of RNASEL with chemical compounds

• Biostable phosphorothioate analogues of 2-5A were synthesized chemically and used to study the effects of naturally occurring mutations and polymorphisms in RNASEL [22].
• Analysis of genotypes revealed that presence of the leucine ELAC2 allele (OR 1.54: 95% CI=0.99-2.41, SS vs. SL, LL) and homozygosity for the glutamic acid RNASEL allele (OR 1.68: 95% CI=1.04-2.70, EE vs. DE, DD) were associated with increased risk [23].
• Cells deficient in RNase L, but not the control cells, were highly resistant to apoptosis by the RNase L activator, 2',5'-oligoadenylate (2-5A) [16].
• Interferon induction of 2-5A-dependent RNAse expression was demonstrated by measuring the mRNA levels in cells treated with interferon and cycloheximide [10].
• The first and second internucleotide linkages are critical for activation of recombinant, human RNase L; A(Rp)ApA, A(Sp)ApA and ApA(Rp)A are agonists (IC50 = 2 x 10(-7), 2 x 10(-6) and 8 x 10(-6) M); ApA(Sp)A is an antagonist [12].

Physical interactions of RNASEL

• Likewise RLI is coimmunoprecipitated with the RNase L complex by a nuclease-specific antibody [20].
• We identify and characterize the human translation termination factor eRF3/GSPT1 as an interacting partner of RNase L [24].
• The cells were returned to monolayer growth for 18 h, and then harvested and assayed to determine the amount of RNase L protein (via [32P]2-5A binding) and the specific activities of RNase L and 2-5A synthetase [25].
• It was also found that the crystal structure of the ankyrin repeat domain L.2-5A complex accurately portrays the 2-5A binding mode in full-length RNase L [26].

Enzymatic interactions of RNASEL

• Similarly, purified, recombinant human 2-5A-dependent ribonuclease was induced to selectively cleave PKR messenger RNA [27].

Regulatory relationships of RNASEL

• RESULTS: Only ELAC2 217L (37% cases vs. 29% controls (P=0.034)) and RNASEL 541E (61% cases vs. 53% controls (P=0.045)) were over-represented [23].
• RNase L inhibitor (RLI) antisense constructions block partially the down regulation of the 2-5A/RNase L pathway in encephalomyocarditis-virus-(EMCV)-infected cells [28].
• Glutathione S-transferase pull-down and co-immunoprecipitation experiments reveal that the androgen receptor and the interferon-activated RNase L interact with each other in a ligand-dependent manner [29].
• Microinjection of an mAb against RNABP into HeLa cells inhibits RNase L antiviral activity and partially inhibits the IFN-alpha/beta-induced antiviral activity [30].
• Caspase-dependent apoptosis by 2',5'-oligoadenylate activation of RNase L is enhanced by IFN-beta [31].

Other interactions of RNASEL

• CONCLUSIONS: These results suggest that, in a European-American population, ELAC2 217L and RNASEL 541E are associated with metastatic sporadic disease [23].
• Several putative prostate cancer candidate genes have also been identified including RNASEL, MSR1, and ELAC2 [32].
• Surprisingly, the RNase L-deficient cells were also highly resistant to apoptosis by combination treatments with a topoisomerase (Topo) I inhibitor (camptothecin, topotecan, or SN-38) and tumor necrosis factor-related apoptosis-inducing ligand [TRAIL (Apo2L)] [16].
• RLI does not lead to 2-5A degradation or to irreversible modification of RNase L [20].
• Susceptibility to WNV disease in inbred strains of mice was mapped to a nonsense mutation in the gene encoding the 1b isoform of 2'-5'-oligoadenylate synthetase (OAS), a member of the OAS/RNase L system of innate viral resistance [33].
• Immunoprecipitation demonstrated that RNase-L mRNA associates with a HuR containing complex in intact cells [34].

Analytical, diagnostic and therapeutic context of RNASEL

• We screened for RNASEL germline mutations in familial prostate cancer patients, and performed a case-control study to examine the association of specific variants with prostate cancer risk in the Japanese. Three variants within the RNASEL gene, G282A, G1385A and T1623G were identified [35].
• Meta-analyses revealed significant associations of prostate cancer with MSR1 IVS7delTTA, -14,742 A>G, and Arg293X in European Americans; Asp174Tyr in African Americans; RNASEL Arg462Gln in European American's overall and in family history-negative disease; and Glu265X in family history-positive European Americans [36].
• The entire RNASEL coding sequence was also screened using denaturing high-performance liquid chromatography and multiplex ligation-dependent probe amplification for possible sequence variations or copy number changes in a population of prostate cancer patients [5].
• In addition, levels of RNase L were established in various normal human tissues and cell types by immunoblotting and immunohistochemistry [3].
• The enzymatically active monomer form of 37-kDa RNase L resolved by 2-D gel electrophoresis has a pI of 6 [11].

References