Department of Cancer Biology
Robert Silverman, Ph.D.
The Mal and Lea Bank Chair
Lerner Research Institute
9500 Euclid Avenue
Cleveland, Ohio 44195
Phone: (216) 445-9650
Fax: (216) 445-6269
Our studies probe fundamental molecular and cellular processes that impact microbial infections and cancer. We seek a better understanding of how the mammalian cell resists viral infections and how the virus antagonizes the host response to infection. Interferons (IFNs) induce a family of 2',5'-oligoadenylate (2-5A) synthetases (OAS). In response to viral double stranded RNA, OAS produces 2-5A whose function is to activate RNase L causing degradation of viral and cellular RNA. Previously we cloned RNase L and established its antiviral activities in genetically deficient mice. We found that RNase L cleaves viral and cellular RNA to generate small RNAs that stimulate IFN synthesis through RIG-I and MDA5. We are currently studying viral and host 2',5'-phosphodiesterases that prevent activation of RNase L, thus allowing virus replication and viral pathogenesis. Our goals include elucidating fundamental events and biologic endpoints surrounding RNase L that impact on viral replication cycles and tumor biology.Another area of research concerns the roles of innate immunity and genetics in prostate cancer. The hereditary prostate cancer 1 (HPC1) gene maps to RNase L. We are investigating the potential role of RNase L in prostate cancer by focusing on basic cellular processes regulated by RNase L including autophagy and apoptosis. We are also developing an experimental protocol for treating late-stage cancer by combining sunitinib treatments with infection by an oncolytic virus.
In other words ...
In other words…. Dr. Silverman has investigated molecular pathways of the anti-viral and anti-cancer activities of interferon for the past 34 years. His studies are mainly focused on a classical innate immune pathway known as the OAS/RNase L system. Interestingly, the RNase L gene maps to the hereditary prostate cancer 1 locus and may have a dual function in both suppressing hereditary prostate cancer and viral infections. The knowledge to be gained from these studies could eventually contribute to improved treatments for viral infections and cancer. For instance, his group has recently shown that transient suppression of the interferon-regulated proteins RNase L and PKR with the drug, sunitinib, enhances the anti-tumor efficacy of a therapeutic virus in mouse models of cancer.
Selected from 228 publications:
Silverman, R.H., Jung, D.D., Nolan-Sorden, N.L., Dieffenbach, C.W., Kedar, V.P., and SenGupta, D. Purification and analysis of murine 2-5A-dependent RNase.J. Biol. Chem. 263, 7336-7341, 1988.
Zhou, A., Hassel, B.A., and Silverman, R.H. Expression cloning of 2-5A-dependent RNase-a uniquely regulated mediator of interferon action. Cell, 72, 753-765, 1993.
Hassel, B.A., Zhou, A., Sotomayor, C., Maran, A., and Silverman, R.H. A dominant negative mutant of 2-5A-dependent RNase suppresses antiproliferative and antiviral effects of interferon. EMBO J., 12, 3297-3304, 1993.
Zhou, A., Paranjape, J., Brown, T.L., Nie, H., Naik, S., Dong, B., Chang, A., Trapp, B. Fairchild, R., Colmenares, C., and Silverman, R.H. Interferon action and apoptosis are defective in mice devoid of 2',5'-oligoadenylate dependent RNase L. EMBO J. 16, 6355-6363,1997.
Der, S., Zhou, A., Williams, B.R.G., and Silverman, R.H.Identification of Genes Differentially Regulated by IFN-α β or γ or Using Oligonucleotide Arrays.Proc. Natl. Acad. Sci. U.S.A 95,15623-15628, 1998.
Zhou, A., Paranjape, J.M., Der, S.D., and Williams, B.R.G. and Silverman, R.H. Novel Innate Mechanisms of Interferon Action are Revealed in Triply Deficient Mice. Virology, 258, 435-440, 1999.
Carpten, J., N., et al. Germline Mutations in the Ribonuclease L (RNase L) Gene in Hereditary Prostate Cancer 1 (HPC1) -Linked Families. Nature Genetics, 30, 181-184, 2002.
Casey, G., et al.RNASEL R462Q variant is implicated in 13% of prostate cancer cases. Nature Genetics, 32, 581-583, 2002. Silverman, R.H. Implications for RNase L in Prostate Cancer Biology.Biochemistry, 42, 1805-1812, 2003.
Xiang, Y., Wang,Z., Murakami, J., Plummer, S., Klein, E.A., Carpten, J., Trent, J., Isaacs W., Casey, G., and Silverman, R. H. Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2',5'-oligoadenylates. Cancer Res. 63: 6795-6801, 2003.
Malathi, K., Paranjape, J.M., Bulanova, E., Shim, M., Guenther-Johnson, J.M., Faber, P.W., Eling, T.E., Williams, B.R.G., and Silverman, R.H. A novel transcriptional signaling pathway in the interferon system mediated by 2'-5'-oligoadenylate activation of RNase L. Proc. Natl. Acad. Sci. U.S.A., 102, 14533-14538, 2005.
Malathi, K., Dong, B., Gale, M., and Silverman, R.H. Small Self RNA Generated by RNase L Amplifies Antiviral Innate Immunity. Nature, 448: 816-819, 2007.
Malathi, K., Saito, T., Crochet, N., Barton, D.J.,Gale, M.and Silverman, R.H. RNase L Releases a Small RNA from HCV RNA that Refolds into a Potent PAMP. RNA, 16: 2108-2119, 2010.
Jha, B.K., Polyakova, I., Kessler, P., Dong, B., Dickerman, B., Sen, G.C., and Silverman, R.H. Inhibition of RNase L and RNA-dependent protein kinase (PKR) by sunitinib impairs antiviral innate immunity. J. Biol. Chem.,286: 26319-26326. 2011.
Zhao, L., Jha, B., Wu, A., Elliott, R., Ziebuhr, J., Gorbalenya, A.E., Silverman, R.H., Weiss, S.R. 2012. Antagonism of the interferon-induced OAS-RNase L pathway by murine coronavirus ns2 protein is required for virus replication and liver pathology. Cell Host and Microbe, 11:607-616, 2012.
Chakrabarti, A., Ghosh, P.K., Banerjee, S., Gaughan, C., and Silverman, R.H. RNase L triggers autophagy in response to viral infections. J. Virol. 86: 11311-21, 2012.
Jha, B.K., Dong, B., Nguyen, C.T., Polyakova, I. and Silverman, R.H. Suppression of antiviral innate immunity by sunitinib enhances oncolyticvirotherapy. Molecular Therapy, Epub, 2013.
Zhao, L., Birdwell, D. Wu, A., Elliott, R., Rose, K., Phillips, J., Li, Y., Grinspan, J., Silverman, R., and Weiss, S. Cell type specific activation of the OAS-RNase L pathway by a murine coronavirus. J. Virol., 87:8408-18, 2013. [Featured article in "JVI Spotlight"]
Sorgeloos, F., Jha, B.K., Silverman, R.H., and Michiels, T.Evasion of antiviral innate immunity by Theiler's virus L* protein through direct inhibition of RNase L.PLoS Pathogens, Epub, 2013.
Zhang, R., Jha, B.K., Ogden, K., Dong, B., Zhao, L., Elliot, R., Patton, J.T., Silverman, R.H.* and Weiss, S.R.* Homologous 2',5'-phosphodiesterases from disparate RNA viruses antagonize antiviral innate immunity. Proc. Natl. Acad. Sci., Epub, 2013. [*Co-corresponding authors].