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BERT JACOBS Professor Ph.D. University of California, Berkeley Send e-mail to bjacobs@asu.edu

Research

Dr. Jacobs came to Arizona State University after four years as a post-doctoral associate and lecturer at the University of California, Santa Barbara. In 1991, he was a Visiting Research Scientist of the National Cancer Institute at the Frederick Cancer Research Center. In 2000 he was Distinguished Visiting Professor at the National Center for Biotechnology, Madrid, Spain. Dr. Jacobs received the Quality Teaching Award from the ASU's College of Liberal Arts and Sciences.

The research interests of Dr. Jacobs revolve around understanding the molecular mechanisms of action of interferon, particularly as they concern control of gene expression at the level of translation.

Interferons are a set of proteins secreted by vertebrate cells in response to virus infection or antigen stimulation. They can interact with non-infected cells and induce in these cells an anti- viral state. That is, replication of most classes of viruses are blocked in interferon-treated cells. Interferon also act to inhibit cell proliferation.

At least some of this block to virus replication is due to induction by interferon of a double stranded RNA-activated protein kinase, PKR. This protein kinase can phosphorylate, and inactivate eukaryotic protein synthesis initiation factor 2, thus preventing synthesis of viral proteins.

Numerous viruses (adenovirus, vaccinia virus, reovirus and Epstein-Barr virus) have been shown to code for inhibitors of the interferon-induced protein kinase. These virus-encoded inhibitors are particularly interested because they allow these viruses to circumvent one of the organisms main defenses against virus infection. They also appear to allow viruses to prevent infected cells from committing suicide in response to the virus infection. Induction of apoptosis (programmed cell death or cellular suicide) by cells appears to be another cellular defense against virus-infection that is inhibited by at least some viruses. Current studies of Dr. Jacobs are aimed at understanding the molecular nature of the vaccinia viral kinase inhibitors, and understanding what role these inhibitors have in replication of these viruses in mammalian cells in culture and in infected animals. We hope that these studies will aid in the development of safer, more effective vaccines for smallpox and other human and animal pathogens.

One of the most interesting set of results from the lab in recent past has to do with the molecular function of one of these kinase inhibitors, the product of the vaccinia virus E3L gene. We have recently shown that this protein binds to Z-form nucleic acid, and that binding to Z-form nucleic acid is essential for pathogenicity of vaccinia virus in a mouse model system. This is the first example of a biological function for Z-DNA/RNA binding and may lead to a better understanding of the role of Z-form nucleic acid in biology.

Since interferons also act to inhibit cell proliferation in addition to inhibiting virus replication, many cancers have evolved to be interferon non-responsive. Thus, many interferon-sensitive viruses preferentially replicate in cancer but not normal cells. We are investigating use of novel interferon-sensitive mutants of vaccinia virus specific anticancer against.

Current Students

Jason Cameron, Ph.D. student, Molecular & Cellular Biology
Stacy Frederick, Ph.D. student, Molecular & Cellular Biology
Kevin Hauns, Ph.D. student, Molecular & Cellular Biology
Susan Holecheck, Ph.D. student, Molecular & Cellular Biology
James Jancovich, Ph.D. candidate, Molecular & Cellular Biology
Garilyn Jentarra, Ph.D. candidate, Molecular & Cellular Biology
Chandra Mitnik, Ph.D. candidate, Microbiology
Matt Pearcy, Ph.D. candidate, Molecular & Cellular Biology
Damien Salmone, Ph.D. student, Molecular & Cellular Biology
Kelly Trainor, Ph.D. candidate, Microbiology

Research Professors

Jeffrey Langland
Karen Kibler

Current Post-docs

Vanessa Lancaster
Michael Heck

Lab Technicians

Connie Chamberlain
Karen Densler

Selected Publications

Jancovich, J. K., J. Mao, V. G. Chinchar, C. Wyatt, S. T. Case, S. Kumar, G. Valente, S. Subramanian, E. W. Davidson, J. P. Collins, and B. L. Jacobs. 2003. Genomic sequence of a ranavirus (family Iridoviridae) associated with salamander mortalities in North America. Virology 316:90-103.

Vijaysri, S., L. Talasela, A. A. Mercer, C. J. McInnes, B. L. Jacobs, and J. O. Langland. 2003. The Orf virus E3L homologue is able to complement deletion of the vaccinia virus E3L gene in vitro but not in vivo. Virology 314:305-14.

Langland, J. O., P. Kao, and B. L. Jacobs. 2003. Regulation of IL-2 gene expression and nuclear factor-90 translocation in vaccinia virus-infected cells. J Interferon Cytokine Res 23:489-500.

Kim, Y. G., M. Muralinath, T. Brandt, M. Pearcy, K. Hauns, K. Lowenhaupt, B. L. Jacobs, and A. Rich. 2003. A role for Z-DNA binding in vaccinia virus pathogenesis. Proc Natl Acad Sci U S A 100:6974-9.

Xiang, Y., R. C. Condit, S. Vijaysri, B. Jacobs, B. R. Williams and R. H. Silverman (2002). "Blockade of interferon induction and action by the E3L double-stranded RNA binding proteins of vaccinia virus." J Virol 76(10): 5251-9.

Langland, J. and B. Jacobs (2002). "The Role of the PKR-Inhibitory Genes, E3L and K3L, in Determining Vaccinia Virus Host Range." Virology 299(1): 133.

He, Y., H. Nakao, S. L. Tan, S. J. Polyak, P. Neddermann, S. Vijaysri, B. L. Jacobs and M. G. Katze (2002). "Subversion of cell signaling pathways by hepatitis C virus nonstructural 5A protein via interaction with Grb2 and P85 phosphatidylinositol 3-kinase." J Virol 76(18): 9207-17.

Jancovich, J. K., E. W. Davids, A. Seiler, B. L. Jacobs and J. P. Collins (2001). "Transmission of the Ambystoma tigrinum virus to alternative hosts." Dis Aquat Organ 46(3): 159-63.

Liu, Y., K. C. Wolff, B. L. Jacobs and C. E. Samuel (2001). "Vaccinia Virus E3L Interferon Resistance Protein Inhibits the Interferon-Induced Adenosine Deaminase A-to-I Editing Activity." Virology 289(2): 378-387.

He, Y., S. L. Tan, S. U. Tareen, S. Vijaysri, J. O. Langland, B. L. Jacobs and M. G. Katze (2001). "Regulation of mRNA translation and cellular signaling by hepatitis C virus nonstructural protein NS5A." J Virol 75(11): 5090-8.

Brandt, T. A. and B. L. Jacobs (2001). "Both carboxy- and amino-terminal domains of the vaccinia virus interferon resistance gene, E3L, are required for pathogenesis in a mouse model." J Virol 75(2): 850-6.

Jacobs, B.L. (2000). Translational Control in Poxvirus-infected Cells. In, Translational Control of Gene Expression, CSHL Press,2000.

Jacobs, B.L. and langland, J.O. (1996). When two strands are better than one: the mediators and modulators of the cellular responses to double-stranded RNA. Virology 219:339-349.

Lyubchenko, Y.L., B.L. Jacobs, S.M. Lindsay, and A. Stasiak. (1995). Atomic force microscopy of nucleoprotein complexes. ScanningMicroscopy 9:705-727.

Chang, H.-W., Uribe, L.H., and Jacobs, B.L. (1995). Rescue of vaccinia virus deleted for the E3L gene by mutants of E3L. J. Virology 69:6605-6608.

Beattie, E, Denzler, K, Tartaglia, J, Paoletti, E, and Jacobs, BL. (1995). Reversal ofthe interferon-sensitive phenotype of an E3L-minus vaccinia virus by expression of the reovirus S4 gene. J. Virology 69 499-505.

Langland, J.O., Song, J., Jacobs, B.L., and Roth, D.A. (1995). A plant-encoded analogue of PKR, the mammalian double-stranded RNA-dependent protein kinase. Plant Phys. 108: 1259- 1267.

Denzler, K. and Jacobs, B.L. (1994). Site-directed mutagenic analysis of reovirus (s3 binding to dsRNA. Virology204:190-199.

Langland, J.O., Pettiford, S.M., Jiang, B. and Jacobs, B.L. (1994). Products of the porcine NSP3 gene bind specifically to double-stranded RNA and inhibit activation of the interferon-induced protein kinase, PKR. J. Virology, 68:3821-3829.

Park H., Davies, M.V., Langland, J.O., Chang, H.-W., Nam, Y.S., Tartaglia, J., Paoletti, E., Jacobs, B.L., Kaufman, R.J., and Venkatesan, S. (1994). A cellular protein that binds several structured viral RNAs is an inhibitor of the interferon induced PKR protein kinase in vitro and in vivo. Proc. Natl Acad Sci, USA, 91:4713 -4717.

Baier, L. Shors, T., Shors, S.T. and Jacobs, B.L. (1993). The mouse phosphotyrosine immunoreactive kinase, TIK, is indistinguishable from the double-stranded RNA-dependent, interferon-inducible protein kinase, PKR. Nucleic Acids Research 21 :4830-4835.

Chang, H.-W., and Jacobs, B.L. (1993). Identification of a conserved motif that is necessary for binding of the vaccinia virus E3L gene products to double-stranded RNA. Virology, 194:537-547.

Davies, M.V., Chang, H.-W., Jacobs, B.L., and Kaufman, R.J. (1993). The E3L and K3L vaccinia virus gene products stimulate translation through inhibition of the double-stranded RNA-activated protein kinase (DAI) by different mechanisms. J. Virology, 67:1688-1692.

Langland, J.O., and Jacobs, B.L. (1992). Cytosolic double-stranded RNA-dependent protein kinase is likely a dimer of partially phosphorylated Mr=66,000 subunits. J. Biol. Chem. 267: 10729-10736.

Chang, H.-W., Watson, J. and Jacobs, B.L. (1992). The vaccinia virus E3L gene encodes a double-stranded RNA-binding protein with inhibitory activity for the interferon-induced protein kinase. Proc. Natl. Acad. Sci. USA 89:4825-4829.