| Identification of 2'-phosphodiesterase, which plays a role in the 2-5A system regulated by interferon. | |
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MedLine Citation:
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PMID: 15231837 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The 2-5A system is one of the major pathways for antiviral and antitumor functions that can be induced by interferons (IFNs). The 2-5A system is modulated by 5'-triphosphorylated, 2',5'-phosphodiester-linked oligoadenylates (2-5A), which are synthesized by 2',5'-oligoadenylate synthetases (2',5'-OASs), inactivated by 5'-phosphatase and completely degraded by 2'-phosphodiesterase (2'-PDE). Generated 2-5A activates 2-5A-dependent endoribonuclease, RNase L, which induces RNA degradation in cells and finally apoptosis. Although 2',5'-OASs and RNase L have been molecularly cloned and studied well, the identification of 2'-PDE has remained elusive. Here, we describe the first identification of 2'-PDE, the third key enzyme of the 2-5A system. We found a putative 2'-PDE band on SDS-PAGE by successive six-step chromatographies from ammonium sulfate precipitates of bovine liver and identified a partial amino acid sequence of the human 2'-PDE by mass spectrometry. Based on the full-length sequence of the human 2'-PDE obtained by in silico expressed sequence tag assembly, the gene was cloned by reverse transcription-PCR. The recombinant human 2'-PDE expressed in mammalian cells certainly cleaved the 2',5'-phosphodiester bond of 2-5A trimer and 2-5A analogs. Because no sequences with high homology to this human 2'-PDE were found, the human 2'-PDE was considered to be a unique enzyme without isoform. Suppression of 2'-PDE by a small interfering RNA and a 2'-PDE inhibitor resulted in significant reduction of viral replication, whereas overexpression of 2'-PDE protected cells from IFN-induced antiproliferative activity. These observations identify 2'-PDE as a key regulator of the 2-5A system and as a potential novel target for antiviral and antitumor treatments. |
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Authors:
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Kazuishi Kubota; Kaori Nakahara; Toshiaki Ohtsuka; Shuku Yoshida; Junko Kawaguchi; Yoko Fujita; Yohei Ozeki; Ayako Hara; Chigusa Yoshimura; Hidehiko Furukawa; Hideyuki Haruyama; Kimihisa Ichikawa; Makoto Yamashita; Tatsuji Matsuoka; Yasuteru Iijima |
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Publication Detail:
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Type: Journal Article Date: 2004-06-30 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 279 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2004 Sep |
Date Detail:
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Created Date: 2004-08-30 Completed Date: 2004-12-10 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 37832-41 Citation Subset: IM |
Affiliation:
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Biomedical Research Laboratories, Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. kkubot@sankyo.co.jp |
| Data Bank Information | |
Bank Name/Acc. No.:
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GENBANK/AB115695 |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenine Nucleotides
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metabolism* Amino Acid Sequence Animals Base Sequence Cattle DNA Primers Exoribonucleases / antagonists & inhibitors, chemistry, metabolism* Hela Cells Humans Liver / enzymology Molecular Sequence Data Oligoribonucleotides / metabolism* Phosphodiesterase Inhibitors / pharmacology Sequence Homology, Amino Acid Virus Replication / drug effects |
| Chemical | |
Reg. No./Substance:
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0/Adenine Nucleotides; 0/DNA Primers; 0/Oligoribonucleotides; 0/Phosphodiesterase Inhibitors; 61172-40-5/2',5'-oligoadenylate; EC 3.1.-/Exoribonucleases; EC 3.1.13.-/2'-phosphodiesterase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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