Document Detail


HIV-1 viral infectivity factor interacts with TP53 to induce G2 cell cycle arrest and positively regulate viral replication.
MedLine Citation:
PMID:  21071676     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Viral infectivity factor, an accessory protein encoded in the HIV-1 genome, induces G2 cell cycle arrest; however, the biological significance and mechanism(s) remain totally unclear. Here we demonstrate that the TP53 pathway is involved in Vif-mediated G2 cell cycle arrest. Vif enhances the stability and transcriptional activity of TP53 by blocking the MDM2-mediated ubiquitination and nuclear export of TP53. Furthermore, Vif causes G2 cell cycle arrest in a TP53-dependent manner. HXB2 Vif lacks these activities toward TP53 and cannot induce G2 cell cycle arrest. Using mutagenesis, we demonstrate that the critical residues for this function are located in the N-terminal region of Vif. Finally, we construct a mutant NL4-3 virus with an NL4-3/HXB2 chimeric Vif defective for the ability to induce cell cycle arrest and show that the mutant virus replicates less effectively than the wild-type NL4-3 virus in T cells expressing TP53. These data imply that Vif induces G2 cell cycle arrest through functional interaction with the TP53/MDM2 axis and that the G2 cell cycle arrest induced by Vif has a positive effect on HIV-1 replication. This report demonstrates the molecular mechanisms and the biological significance of Vif-mediated G2 cell cycle arrest for HIV-1 infection.
Authors:
Taisuke Izumi; Katsuhiro Io; Masashi Matsui; Kotaro Shirakawa; Masanobu Shinohara; Yuya Nagai; Masahiro Kawahara; Masayuki Kobayashi; Hiroshi Kondoh; Naoko Misawa; Yoshio Koyanagi; Takashi Uchiyama; Akifumi Takaori-Kondo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-11-11
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-12-01     Completed Date:  2011-01-05     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  20798-803     Citation Subset:  IM    
Affiliation:
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
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MeSH Terms
Descriptor/Qualifier:
G2 Phase*
HCT116 Cells
HIV Infections / metabolism*,  pathology*
HIV-1 / physiology*
Humans
Protein Stability
Proto-Oncogene Proteins c-mdm2 / metabolism
Signal Transduction
Structure-Activity Relationship
T-Lymphocytes / virology
Tumor Suppressor Protein p53 / metabolism*
Virus Replication / physiology*
vif Gene Products, Human Immunodeficiency Virus / chemistry,  metabolism*
Chemical
Reg. No./Substance:
0/Tumor Suppressor Protein p53; 0/vif Gene Products, Human Immunodeficiency Virus; EC 6.3.2.19/MDM2 protein, human; EC 6.3.2.19/Proto-Oncogene Proteins c-mdm2
Comments/Corrections

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