Annual Report 2011 - Center for Advanced Biotechnology and ...

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Dr. Masayori Inouye CABM Resident Faculty Member Distinguished Professor Department of Biochemistry UMDNJ-Robert Wood Johnson Medical School Dr. Sangita Phadtere Adjunct Associate Professor Yojiro Ishida Research Associate Hiroshi Kobayashi Research Associate Dr. Lili Mao Research Associate Dr. Yoshihiro Yamaguchi Research Associate Dr. Kuen-Phon Wu Postdoctoral Associate Dr. Hisako Masuda Postdoctoral Fellow Yu-Jen Chen Graduate Student Chun-Yi Lin Graduate Student Bacterial Physiology and Protein Engineering Laboratory Dr. Masayori Inouye joined CABM in October 2009. He is well-known for his discovery of antisense-RNA in 1984, the function of the signal peptide for secretion, biogenesis of outer membrane proteins, propeptide-mediated protein folding and molecular biology of histidine kinases. Currently he is working on the characterization of the toxin-antitoxin (TA) systems from E. coli and human pathogens such as Mycobacterium tuberculosis and Staphylococcus aureus. The discovery of a sequence (ACA)-specific endoribonuclease from the E. coli TA systems led his laboratory to develop a unique protein production system converting E. coli cells to a single-protein production (SPP) bioreactor. This system allows one to label only a protein of interest in the cells with a specific isotope(s), an amino acid(s) or a toxic non-natural amino acid analogue(s) in a high yield. His laboratory also does research on the mechanism of ribosome stalling during protein synthesis. In May 2011, he received the Edward J. Ill Excellence in Medicine Award for Outstanding Medical Research Scientist. Dr. Inouye is a member of the American Academy of Arts & Sciences. Toxin-antitoxin (TA) systems; their roles in bacterial physiology and the development of novel antibiotics Almost all bacteria including human pathogens contain suicide or toxin genes which are induced under stress conditions leading to cell growth arrest and eventual cell death in a way similar to apoptosis or programmed cell death in higher systems. Escherichia coli contains at least 35 TA systems and their toxins are highly diverse, targeting DNA, mRNA, protein and cell wall synthesis. The importance of these TA systems in medical science has not been fully appreciated until recently. The Inouye laboratory works to decipher the cellular targets of these toxins and the molecular mechanisms of toxin functions. Promoter ATP-dependent proteases Antitoxin Toxin Cellular targets Bacterial Toxin-Antitoxin (Apoptosis) System Protein DNA 15
mRNA interferases mRNA interferases are encoded by one of the TA systems. MazF from E. coli is the first mRNA interferase discovered in Dr. Inouye’s laboratory and functions as a sequence-specific (ACA) endoribonuclease. Its induction in E. coli cells results in growth arrest and eventual cell death. The Inouye group also observed that MazF induction in mammalian cells effectively causes Bak (a pro-apoptotic protein)-dependent programmed cell death. The application of bacterial mRNA interferases for mammalian cell growth regulation is currently being explored to develop an effective, novel method for cancer treatment and HIV eradication. In addition to E. coli MazF, the laboratory has identified a large number of mRNA interferases having different RNA cleavage specificity, including one from a highly halophilic archaeon that cleaves a specific seven base sequence. mRNA interference using highly sequence-specific mRNA interferases instead of antisense RNA or RNAi may be a novel and exciting way to regulate gene expression. Single protein production in living cells Expression of MazF, an ACA-specific mRNA interferase, results in nearly complete degradation of cellular mRNAs, leading to almost complete inhibition of protein synthesis. Intriguingly, MazF-induced cells are still fully capable of producing a protein at a high level if the mRNA for that protein is engineered to have no ACA sequences without altering its amino acid sequence. Therefore, it is possible to convert E. coli cells into a bioreactor producing a single protein of interest. This “single-protein production” (SPP) system allows NMR structural studies of proteins without purification, which makes this system especially useful for structural studies of membrane proteins. In addition, the SPP system provides a unique opportunity to produce proteins in which all the residues of a specific amino acid in a protein are replaced with toxic non-natural amino acid analogues to create proteins of novel structures and functions. Publications: Awano, N., Rajagopal, V., Arbing, M., Patel, S., Hunt, J., Inouye, M., Phadtare, S. Escherichia coli RNase R has dual activities, helicase and ribonuclease. J. Bacteriol. 2010 192(5):1344-52. Peng, Y.Y., Yoshizumi, A., Danon, S.J., Glattauer, V., Prokopenko, O., Mirochinitchenko, O., Yu, Z., Inouye, M., Werkmeister, J.A., Brodsky, B., Ramshaw, J.A. A Streptococcus pyogenes derived collagen-like protein as a noncytotoxic and non-immunogenic cross-linkable biomaterial. Biomaterials 2010 31(10):2755-61. Jung-Ho Park Graduate Student Narumi Tokunaga Graduate Student Zhuoxin Yu Graduate Student Dr. Qian Tan Research Teaching Spec. Chun Ying Xu Research Teaching Spec. Dr. Yoshihiro Yamaguchi Research Teaching Spec. Dr. Yong Long Zhang Research Teaching Spec. Xushen Chen Lab Technician 16
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Page 4 and 5: Director’s Overview CABM—25 and
Page 6 and 7: of Health, National Science Foundat
Page 8 and 9: Cell & Developmental Biology Labora
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Page 12 and 13: Dr. Céline Gélinas CABM Resident
Page 14 and 15: (CHINJ, CINJ and CABM) and Lauri Go
Page 18 and 19: Xu, Z., Mirochnitchenko, O., Xu, C.
Page 20 and 21: Dr. Fang Liu CABM Resident Faculty
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Page 24 and 25: In the prior year, we have made con
Page 26 and 27: Dr. James Millonig CABM Resident Fa
Page 28 and 29: We have mapped 5 different vl modif
Page 30 and 31: Dr. Arnold Rabson Director Child He
Page 32 and 33: Publications: Zheng, X., Cui, X.X.,
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Page 36 and 37: Dr. Mengqing Xiang CABM Resident Fa
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Page 40 and 41: Laboratory Faculty Director Structu
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Dr. Ann M. Stock Associate Director
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Publications: Barbieri, C.M., Mack,
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Lectures and Seminars 69
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CABM RETREAT, June 30, 2011 Cook Ca
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25 th Anniversary CABM Symposium Fr
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Edery Lab Joseph Albistur George Gh
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PATENTS P. Lobel, et al. “Methods
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Montelione, G.T., Ma, L. and Krug,
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Outside Academic Members Dr. Wayne
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Former CABM Scientific Advisory Boa
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Fiscal Information 86
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Anderson, Stephen Rutgers CABM Gran
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Leukemia & Lymphoma Society BFL-1 a
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Total Award Start - End FY 2011 Dir
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Department of Defense Tumor suppres
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Total Award Start - End FY 2011 Dir
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