2001 - Center for Advanced Biotechnology and Medicine - Rutgers ...

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Collaborative studies with Drs. Strair (CINJ) and White (CABM) are evaluating the potential utility of highly attenuated adenoviruses as cytotoxic agents for the therapy of different subsets of leukemias and lymphomas since mutated, highly attenuated adenoviruses may be __________________________________________________________________________________ Center for Advanced Biotechnology and Medicine Arnold B. Rabson useful in the therapy of this disease. In collaboration with Dr. R. Strair (CINJ) and Dr. A. Conney (Rutgers University), Dr. Rabson is studying the molecular mechanisms by which the phorbol ester, TPA, can induce differentiation of human leukemic cells. The collaborative studies at CABM have focused on the effects of TPA on NF-kB and on chromatin structure during the induction of differentiation. The Rabson laboratory has identified and characterized models of latent HTLV-1 infection and demonstrated that immune activation stimuli can potently induce HTLV-1 gene expression. This suggests that stimulation of particular T cell clones through their T cell receptor could lead to enhanced HTLV-1 gene expression, resulting in increased T cell proliferation. This could explain the polyclonal to oligoclonal proliferation of infected T cells that characterizes HTLV-1associated diseases. Over the last year, Dr. Rabson’s laboratory has demonstrated that the HTLV-1 Tax protein is the target of the T cell activation stimuli. These results suggest that inhibition of T cell signaling might alter the progression of HTLV-1 infection. Publications: Rabson, A.B. and Lin, H.-C. (2000). NF-kappaB and HIV: Linking Viral and Immune Activation. Adv. Pharm. 48:161-207. Rabson, A.B., Padarathsingh, M. and Le Beau, M. (2000). Molecular Biology and Experimental Models for Hematologic Malignant Diseases: Workshop of the NIH Pathology B Study Section. Biochim. Biophys. Acta Reviews on Cancer, B R1-R7. Ke S, Rabson A.B., Germino J.F., Gallo M.A. and Tian Y. (2001). Mechanism of Suppression of Cytochrome P-450 1A1 Expression by Tumor Necrosis Factor-alpha and Lipopolysaccharide. J. Biol. Chem. 276:39638-39644, 2001. Zheng, X., Chang, R.L., Cui, X.-X., Kelly, K.A., Strair, R., Suh, J., Han, Z.T., Rabson, A. and Conney, A.H. (2001). Synergistic effects of clinically achievable concentrations of 12-Otetradecanoylphorbol-13-acetate in combination with all-trans retinoic acid, 1α, 25dihydroxyvitamin D 3 and sodium butyrate on differentiation of HL-60 cells. Oncol Res. 12:419- 27. 40
Aaron J. Shatkin, Ph.D. Director, CABM; University Professor of Molecular Biology at Rutgers University and Professor, UMDNJ-Robert Wood Johnson Medical School, Department of Molecular Genetics and Microbiology Molecular Virology Laboratory Dr. Aaron J. Shatkin, a member of the National Academy of Sciences, has held research positions at the National Institutes of Health, The Salk Institute, and the Roche Institute of Molecular Biology. He has taught at, among other institutions, Georgetown University Medical School, Cold Spring Harbor Laboratory, The Rockefeller University, UMDNJ-Newark Medical School, University of Puerto Rico, and Princeton University. He was editor of the Journal of Virology from 1973-1977, founding editor-in-chief of Molecular and Cellular Biology from 1980-1990, and is currently an editor of Advances in Virus Research and a member of the editorial board of the Proceedings of the National Academy of Sciences. Shatkin serves on the advisory boards of a number of organizations including the Howard Hughes Medical Institute, and in 1989 he was recognized by New Jersey Monthly magazine with a New Jersey Pride Award for his contributions to the State’s economic development. In 1991 the State of N.J. awarded Shatkin the Thomas Alva Edison Science Award. He was elected Fellow of the American Academy of Arts and Sciences in 1997, and the American Association for the Advancement of Science in 1999. One of the earliest steps in the cascade of controls that regulate mRNA formation and function is the addition of a 5'-terminal "cap." This structural hallmark is present on all eukaryotic cellular mRNAs and is essential for viability. The cap enhances several downstream events in gene expression including splicing of pre-mRNAs, initiation of protein synthesis and mRNA stability. Recently we have cloned and sequenced the mouse and human capping enzymes (CE) and mapped the human protein to 6q16, a region implicated in tumor suppression. The mammalian CE are 597-aa polypeptides consisting of two functional domains, N-terminal RNA 5' triphosphatase (RT) and C-terminal guanylyltransferase (GT). Mutational analysis demonstrated that the GT active site lysine is present in one of several highly conserved motifs characteristic of a nucleotidyltransferase superfamily. A haploid strain of S. cerevisiae lacking GT was complemented for growth by the mouse wild type cDNA clone but not by a clone containing alanine in place of the active-site lysine. The results demonstrate the functional conservation of CE from yeast to mammals. We found that mammalian CE binds via its GT domain to the hyperphosphorylated C-terminal domain (P-CTD) of RNA polymerase II,accounting for the selective capping of pre-mRNAs. The CE N-terminal RT contains the sequenceVHCTHGFNRTG which corresponds to the conserved active-site motif in protein tyrosine phosphatases (PTPs). Mutational analyses indicate that removal of phosphate from RNA 5' ends and from protein tyrosines occurs by a similar mechanism. We have also cloned, mapped to 18p11.22-p11.23 and characterized the third essential enzyme for capping--mRNA (guanine-7-) methyltransferase (MT). Sequence alignment of the 476-aa human MT with the corresponding yeast, worm and fly enzymes demonstrated several required, conserved motifs including one for binding S-adenosylmethionine. Yeast two-hybrid screening with CE yielded transcription elongation factor SPT5 which stimulated GT, but the effects were not additive with SPT5, suggesting a common binding site __________________________________________________________________________________ Center for Advanced Biotechnology and Medicine 41
Page 1 and 2: C A B M Center for Advanced Biotech
Page 3 and 4: Director’s Overview The community
Page 5 and 6: Research Programs and Laboratories
Page 7 and 8: Cory Abate-Shen, Ph.D. Resident Fac
Page 9 and 10: Isaac Edery, Ph.D. Resident Faculty
Page 11 and 12: Céline Gélinas, Ph.D. Resident Fa
Page 13 and 14: Fang Liu, Ph.D. Resident Faculty Me
Page 15 and 16: Peter Lobel, Ph.D. Resident Faculty
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Page 21 and 22: Eileen White, Ph.D. Associate Inves
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Page 31 and 32: Gaetano Montelione, Ph.D. Resident
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Page 39: Arnold B. Rabson, M.D. Resident Fac
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Page 45 and 46: January 24 James Manley, Biological
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