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1 Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University; 2 ARC Centre of Excellence for Biotechnology and Development, Clayton, Victoria, Australia; and 3 Center for Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, P.R. China
Requests for reprints: David A. Jans, Nuclear Signaling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, P.O. Box 13D, Clayton, Victoria 3800, Australia. Phone: 00613/99053778; Fax: 00613/99054699; E-mail: David.Jans{at}med.monash.edu.au.
Tumor cellspecific activity of chicken anemia virus viral protein 3 (VP3 or apoptin) is believed to be dependent on its ability to localize in the nucleus of transformed but not of primary or nontransformed cells. The present study characterizes the signals responsible for the novel nucleocytoplasmic trafficking properties of VP3 using two isogenic tumor/nontumor cell pairs. In addition to the tumor cellspecific nuclear targeting signal, comprising two stretches of basic amino acids in the VP3 COOH terminus which are highly efficient in tumor but not in normal cells, we define the CRM1-recognized nuclear export sequence (NES) within the VP3 tumor cellspecific nuclear targeting signal for the first time. Intriguingly, the NES (amino acids 97-105) is functional in normal but not in tumor cells through the action of the threonine 108 phosphorylation site adjacent to the NES which inhibits its action. In addition, we characterize a leucine-rich sequence (amino acids 33-46) that assists VP3 nuclear accumulation by functioning as a nuclear retention sequence, conferring association with promyelocytic leukemia nuclear bodies. This unique combination of signals is the basis of the tumor cellspecific nuclear targeting abilities of VP3.
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G. W. Moseley, X. Lahaye, D. M. Roth, S. Oksayan, R. P. Filmer, C. L. Rowe, D. Blondel, and D. A. Jans Dual modes of rabies P-protein association with microtubules: a novel strategy to suppress the antiviral response J. Cell Sci., October 15, 2009; 122(20): 3652 - 3662. [Abstract] [Full Text] [PDF] |
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G. Alvisi, D. M. Roth, D. Camozzi, G. S. Pari, A. Loregian, A. Ripalti, and D. A. Jans The Flexible Loop of the Human Cytomegalovirus DNA Polymerase Processivity Factor ppUL44 Is Required for Efficient DNA Binding and Replication in Cells J. Virol., September 15, 2009; 83(18): 9567 - 9576. [Abstract] [Full Text] [PDF] |
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S. M. Rawlinson, M. J. Pryor, P. J. Wright, and D. A. Jans CRM1-mediated Nuclear Export of Dengue Virus RNA Polymerase NS5 Modulates Interleukin-8 Induction and Virus Production J. Biol. Chem., June 5, 2009; 284(23): 15589 - 15597. [Abstract] [Full Text] [PDF] |
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S. Maddika, S. Panigrahi, E. Wiechec, S. Wesselborg, U. Fischer, K. Schulze-Osthoff, and M. Los Unscheduled Akt-Triggered Activation of Cyclin-Dependent Kinase 2 as a Key Effector Mechanism of Apoptin's Anticancer Toxicity Mol. Cell. Biol., March 1, 2009; 29(5): 1235 - 1248. [Abstract] [Full Text] [PDF] |
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E. Sinigalia, G. Alvisi, B. Mercorelli, D. M. Coen, G. S. Pari, D. A. Jans, A. Ripalti, G. Palu, and A. Loregian Role of Homodimerization of Human Cytomegalovirus DNA Polymerase Accessory Protein UL44 in Origin-Dependent DNA Replication in Cells J. Virol., December 15, 2008; 82(24): 12574 - 12579. [Abstract] [Full Text] [PDF] |
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G. W. Moseley, D. M. Roth, M. A. DeJesus, D. L. Leyton, R. P. Filmer, C. W. Pouton, and D. A. Jans Dynein Light Chain Association Sequences Can Facilitate Nuclear Protein Import Mol. Biol. Cell, August 1, 2007; 18(8): 3204 - 3213. [Abstract] [Full Text] [PDF] |
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D. W. Heilman, J. G. Teodoro, and M. R. Green Apoptin Nucleocytoplasmic Shuttling Is Required for Cell Type-Specific Localization, Apoptosis, and Recruitment of the Anaphase-Promoting Complex/Cyclosome to PML Bodies. J. Virol., August 1, 2006; 80(15): 7535 - 7545. [Abstract] [Full Text] [PDF] |
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