RNase L dimerization in a mammalian two-hybrid system in response to 2',5'-oligoadenylates

Naik, Sharon; Paranjape, Jayashree M.; Silverman, Robert H.

doi:10.1093/nar/26.6.1522

Cited by 28 publications

(16 citation statements)

References 22 publications

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“…All OAS, except OASL, are interferon-induced proteins characterised by their capacity to catalyse the synthesis of 2ʹ-5ʹ-linked oligomers of adenosine from adenosine triphosphate (2-5A) [11,12] . The 2-5A binds to a latent Ribonuclease L (RNase L), which subsequently dimerises into its active form [13][14][15] . It was shown that the suppression of RNase L activity in cancer cell lines dramatically blocked cell death, which supports its role as a strong inducer of apoptosis [16,17] .…”

Section: Introductionmentioning

confidence: 99%

Oligoadenylate synthetase 1 (OAS1) expression in human breast and prostate cancer cases, and its regulation by sex steroid hormones

Maia¹,

Rocha²,

Socorro³

et al. 2016

Adv Mod Oncol Res

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Oligoadenylate synthetase 1 (OAS1) is an interferon-induced protein characterised by its capacity to catalyse the synthesis of 2ʹ-5ʹ-linked oligomers of adenosine from adenosine triphosphate (2-5A). The 2-5A binds to a latent Ribonuclease L (RNase L), which subsequently dimerises into its active form and may play an important role in the control of cell growth, differentiation and apoptosis. Previously, our research group identified OAS1 as a differentially-expressed gene in breast and prostate cancer cell lines when compared to normal cells. This study evaluates: i) the expression of OAS1 in human breast and prostate cancer specimens; and ii) the effect of sex steroid hormones in regulating the expression of OAS1 in breast (MCF-7) and prostate (LNCaP) cancer cell lines. The obtained results showed that OAS1 expression was down-regulated in human infiltrative ductal carcinoma of breast, adenocarcinoma of prostate, and benign prostate hyperplasia, both at mRNA and protein level. In addition, OAS1 expression was negatively correlated with the progression of breast and prostate cancer. With regards to the regulation of OAS1 gene, it was demonstrated that 17β-estradiol (E 2 ) down-regulates OAS1 gene in MCF-7 cell lines, an effect that seems to be dependent on the activation of oestrogen receptor (ER). On the other hand, 5α-dihydrotestosterone (DHT) treatment showed no effect on the expression of OAS1 in LNCaP cell lines. The lower levels of OAS1 in breast and prostate cancer cases indicated that the OAS1/RNaseL apoptotic pathway may be compromised in breast and prostate tumours. Moreover, the present findings suggested that this effect may be enhanced by oestrogen in ER-positive breast cancers.Keywords: OAS1; oestrogen; androgen; breast cancer; prostate cancer Citation: Maia CJ, Rocha SM, Socorro S, Schmitt F, Santos CR. Oligoadenylate synthetase 1 (OAS1) expression in human breast and prostate cancer cases, and its regulation by sex steroid hormones. Adv Mod Oncol Res 2016; 2(2): 97-104; http://dx

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Section: Introductionmentioning

confidence: 99%

Oligoadenylate synthetase 1 (OAS1) expression in human breast and prostate cancer cases, and its regulation by sex steroid hormones

Maia¹,

Rocha²,

Socorro³

et al. 2016

Adv Mod Oncol Res

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“…With ATP as substrate these enzymes produce 5′-phosphorylated 2′-5′ linked oligoadenylates (2-5A), which activate RNase L by binding to the ankyrin repeats and inducing dimerization, essential for the endonuclease activity of RNase L [8].…”

Section: Introductionmentioning

confidence: 99%

Germline Mutation in RNASEL Predicts Increased Risk of Head and Neck, Uterine Cervix and Breast Cancer

et al. 2008

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The BackgroundRibonuclease L (RNASEL), encoding the 2′-5′-oligoadenylate (2-5A)-dependent RNase L, is a key enzyme in the interferon induced antiviral and anti-proliferate pathway. Mutations in RNASEL segregate with the disease in prostate cancer families and specific genotypes are associated with an increased risk of prostate cancer.Infection by human papillomavirus (HPV) is the major risk factor for uterine cervix cancer and for a subset of head and neck squamous cell carcinomas (HNSCC). HPV, Epstein Barr virus (EBV) and sequences from mouse mammary tumor virus (MMTV) have been detected in breast tumors, and the presence of integrated SV40 T/t antigen in breast carcinomas correlates with an aggressive phenotype and poor prognosis.A genetic predisposition could explain why some viral infections persist and induce cancer, while others disappear spontaneously. This points at RNASEL as a strong susceptibility gene.Methodology/Principal FindingsTo evaluate the implication of an abnormal activity of RNase L in the onset and development of viral induced cancers, the study was initiated by searching for germline mutations in patients diagnosed with uterine cervix cancer. The rationale behind is that close to 100% of the cervix cancer patients have a persistent HPV infection, and if a defective RNase L were responsible for the lack of ability to clear the HPV infection, we would expect to find a wide spectrum of mutations in these patients, leading to a decreased RNase L activity. The HPV genotype was established in tumor DNA from 42 patients diagnosed with carcinoma of the uterine cervix and somatic tissue from these patients was analyzed for mutations by direct sequencing of all coding and regulatory regions of RNASEL. Fifteen mutations, including still uncharacterized, were identified. The genotype frequencies of selected single nucleotide polymorphisms (SNPs) established in the cervix cancer patients were compared between 382 patients with head and neck squamous cell carcinomas (HNSCC), 199 patients with primary unilateral breast cancer and 502 healthy Danish control individuals. We found that the genotype frequencies of only one of the 15 mutations, the yet uncharacterized 5′UTR mutation rs3738579 differed significantly between cancer patients and control individuals (P-value: 4.43×10−5).Conclusion/SignificanceIn conclusion, we have discovered an increased risk, a heterozygous advantage and thereby a protective effect linked to the RNASEL SNP rs3738579. This effect is found for patients diagnosed with carcinoma of the uterine cervix, HNSCC, and breast cancer thus pointing at RNASEL as a general marker for cancer risk and not restricted to familial prostate cancer.

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“…We also showed that Tyr712 and Phe716 in this region are significantly involved in RNA binding and catalysis 9. The C‐terminal 80 residues and Lys392 are critical for dimerization,7, 10, 11 with mutants in these sites showing no dimerization or RNase activity despite normal 2‐5A binding ability.…”

Section: Introductionmentioning

confidence: 76%

“…Second, ANK is thought not to dimerize by itself, as GST‐ANK (residues 1–342) does not bind to RNase L in the presence of 2‐5A,7 and His‐ANK complexed with pApApA was shown to be a monomer by crystal structure analysis 17. Third, the dimerization sites are thought to lie in both the C‐terminal 80 residues and the protein kinase domain 10, 11. At least one of these dimerization sites should appear only after 2‐5A binding.…”

Section: Discussionmentioning

confidence: 99%

2‐5A induces a conformational change in the ankyrin‐repeat domain of RNase L

2005

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RNase L is responsible for the 2-5A host defense system, an RNA degradation pathway present in cells of higher vertebrates that functions in both the antiviral and anticellular activities of interferon. The activity of RNase L is tightly regulated and is exerted only in the presence of 2-5A. The postulated mechanism of its regulation is as follows: the N-terminal half ankyrin-repeat domain masks the C-terminal half nuclease domain in the absence of 2-5A. On binding 2-5A at the ankyrin-repeat domain, RNase L forms a homodimer and removes the ankyrin-repeat domain from the nuclease domain to become the active form. A conformational change in the ankyrin-repeat domain is a key step in this hypothetical mechanism, but there is as yet no evidence for such a change. To clarify the events induced by 2-5A binding, we established procedures for expression and purification of the ankyrin-repeat domain of human RNase L. Fluorescence spectra of the protein showed clear difference in the presence and absence of 2-5A. The alterations in the spectra supported conformational changes of the protein. Time-resolved anisotropy measurements indicated that 2-5A binding led to a significant decrease in the rotational radius of the protein. In addition, 2-5A provided the domain with resistance to protease digestion as a result of a conformational change. These results indicated that the ankyrin-repeat domain of RNase L constricts its structure by binding of 2-5A. This observation suggests a revised model of the 2-5A-induced activation of RNase L.

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RNase L dimerization in a mammalian two-hybrid system in response to 2',5'-oligoadenylates

Cited by 28 publications

References 22 publications

Oligoadenylate synthetase 1 (OAS1) expression in human breast and prostate cancer cases, and its regulation by sex steroid hormones

Oligoadenylate synthetase 1 (OAS1) expression in human breast and prostate cancer cases, and its regulation by sex steroid hormones

Germline Mutation in RNASEL Predicts Increased Risk of Head and Neck, Uterine Cervix and Breast Cancer

2‐5A induces a conformational change in the ankyrin‐repeat domain of RNase L

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