This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xiang, Y. Articles by Silverman, R. H. Search for Related Content PubMed PubMed Citation Articles by Xiang, Y. Articles by Silverman, R. H.

Effects of RNase L Mutations Associated with Prostate Cancer on Apoptosis Induced by 2',5'-Oligoadenylates¹

Department of Cancer Biology, Lerner Research Institute [Y. X., Z. W., J. M., S. P., G. C., R. H. S.], and Urological Institute [E. A. K.], Cleveland Clinic Foundation, Cleveland, Ohio 44195; Translational Genomics Research Institute, Phoenix, Arizona 85004 [J. D. C., J. M. T.]; and Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287 [W. B. I.]

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.

This article has been cited by other articles:

				V. C. Lombardi, F. W. Ruscetti, J. Das Gupta, M. A. Pfost, K. S. Hagen, D. L. Peterson, S. K. Ruscetti, R. K. Bagni, C. Petrow-Sadowski, B. Gold, et al. Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome Science, October 23, 2009; 326(5952): 585 - 589. [Abstract] [Full Text] [PDF]

				S. Kim, N. Kim, B. Dong, D. Boren, S. A. Lee, J. Das Gupta, C. Gaughan, E. A. Klein, C. Lee, R. H. Silverman, et al. Integration Site Preference of Xenotropic Murine Leukemia Virus-Related Virus, a New Human Retrovirus Associated with Prostate Cancer J. Virol., October 15, 2008; 82(20): 9964 - 9977. [Abstract] [Full Text] [PDF]

				R. H. Silverman Viral Encounters with 2',5'-Oligoadenylate Synthetase and RNase L during the Interferon Antiviral Response J. Virol., December 1, 2007; 81(23): 12720 - 12729. [Full Text] [PDF]

				S. J. Shook, J. Beuten, K. C. Torkko, T. L. Johnson-Pais, D. A. Troyer, I. M. Thompson, and R. J. Leach Association of RNASEL Variants with Prostate Cancer Risk in Hispanic Caucasians and African Americans Clin. Cancer Res., October 1, 2007; 13(19): 5959 - 5964. [Abstract] [Full Text] [PDF]

				X. Liu, F. R. Schumacher, S. J. Plummer, E. Jorgenson, G. Casey, and J. S. Witte trans-Fatty acid intake and increased risk of advanced prostate cancer: modification by RNASEL R462Q variant Carcinogenesis, June 1, 2007; 28(6): 1232 - 1236. [Abstract] [Full Text] [PDF]

				B. Dong, S. Kim, S. Hong, J. Das Gupta, K. Malathi, E. A. Klein, D. Ganem, J. L. DeRisi, S. A. Chow, and R. H. Silverman From the Cover: An infectious retrovirus susceptible to an IFN antiviral pathway from human prostate tumors PNAS, January 30, 2007; 104(5): 1655 - 1660. [Abstract] [Full Text] [PDF]

				H. Li and B. C. Tai RNASEL Gene Polymorphisms and the Risk of Prostate Cancer: a Meta-analysis. Clin. Cancer Res., October 1, 2006; 12(19): 5713 - 5719. [Abstract] [Full Text] [PDF]

				S. V. Scherbik, J. M. Paranjape, B. M. Stockman, R. H. Silverman, and M. A. Brinton RNase L Plays a Role in the Antiviral Response to West Nile Virus J. Virol., March 15, 2006; 80(6): 2987 - 2999. [Abstract] [Full Text] [PDF]

				A. Orr-Urtreger, A. Bar-Shira, D. Bercovich, N. Matarasso, U. Rozovsky, S. Rosner, S. Soloviov, G. Rennert, L. Kadouri, A. Hubert, et al. RNASEL Mutation Screening and Association Study in Ashkenazi and Non-Ashkenazi Prostate Cancer Patients. Cancer Epidemiol. Biomarkers Prev., March 1, 2006; 15(3): 474 - 479. [Abstract] [Full Text] [PDF]

				J. Spence, B. M. Duggan, C. Eckhardt, M. McClelland, and D. Mercola Messenger RNAs under Differential Translational Control in Ki-ras-Transformed Cells Mol. Cancer Res., January 1, 2006; 4(1): 47 - 60. [Abstract] [Full Text] [PDF]

				D. J. Bettoun, A. Scafonas, S. J. Rutledge, P. Hodor, O. Chen, C. Gambone, R. Vogel, S. McElwee-Witmer, C. Bai, L. Freedman, et al. Interaction between the Androgen Receptor and RNase L Mediates a Cross-talk between the Interferon and Androgen Signaling Pathways J. Biol. Chem., November 25, 2005; 280(47): 38898 - 38901. [Abstract] [Full Text] [PDF]

				K. Malathi, J. M. Paranjape, E. Bulanova, M. Shim, J. M. Guenther-Johnson, P. W. Faber, T. E. Eling, B. R. G. Williams, and R. H. Silverman A transcriptional signaling pathway in the IFN system mediated by 2'-5'-oligoadenylate activation of RNase L PNAS, October 11, 2005; 102(41): 14533 - 14538. [Abstract] [Full Text] [PDF]

				H. Rennert, C. M. Zeigler-Johnson, K. Addya, M. J. Finley, A. H. Walker, E. Spangler, D. G.B. Leonard, A. Wein, S. B. Malkowicz, and T. R. Rebbeck Association of Susceptibility Alleles in ELAC2/HPC2, RNASEL/HPC1, and MSR1 with Prostate Cancer Severity in European American and African American Men Cancer Epidemiol. Biomarkers Prev., April 1, 2005; 14(4): 949 - 957. [Abstract] [Full Text] [PDF]

				K. Malathi, J. M. Paranjape, R. Ganapathi, and R. H. Silverman HPC1/RNASEL Mediates Apoptosis of Prostate Cancer Cells Treated with 2',5'-Oligoadenylates, Topoisomerase I Inhibitors, and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Cancer Res., December 15, 2004; 64(24): 9144 - 9151. [Abstract] [Full Text] [PDF]

				F. Wiklund, B.-A. Jonsson, A. J. Brookes, L. Stromqvist, J. Adolfsson, M. Emanuelsson, H.-O. Adami, K. Augustsson-Balter, and H. Gronberg Genetic Analysis of the RNASEL Gene in Hereditary, Familial, and Sporadic Prostate Cancer Clin. Cancer Res., November 1, 2004; 10(21): 7150 - 7156. [Abstract] [Full Text] [PDF]