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PMID:16540471

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Citation

Imai, K and Okamoto, T (2006) Transcriptional repression of human immunodeficiency virus type 1 by AP-4. J. Biol. Chem. 281:12495-505

Abstract

Elucidation of the mechanism of transcriptional silencing of human immunodeficiency virus type 1 (HIV-1) provirus in latently infected cells is crucial to understand the pathophysiology of HIV-1 infection and to develop novel therapies. Here we demonstrate that AP-4 is responsible for the transcriptional repression of HIV-1. We found that AP-4 site within the viral long terminal repeat (LTR) is well conserved in the majority of HIV-1 subtypes and that AP-4 represses HIV-1 gene expression by recruiting histone deacetylase (HDAC) 1 as well as by masking TATA-binding protein to TATA box. AP-4-mediated transcriptional repression was inhibited by an HDAC inhibitor, tricostatin A, and could be exerted even at distant locations from the TATA box. In addition, AP-4 interacted with HDAC1 both in vivo and in vitro. Moreover, chromatin immunoprecipitation assays have revealed that AP-4 and HDAC1 are present in the HIV-1 LTR promoter in latently infected ACH2 and U1 cells, and they are dissociated from the promoter concomitantly with the association of acetylated histone H3, TBP, and RNA polymerase II upon TNF-alpha stimulation of HIV-1 replication. Furthermore, when AP-4 is knocked down by siRNA, HIV-1 production was greatly augmented in cells transfected with a full-length HIV-1 clone. These results suggest that AP-4 may be responsible for transcriptional quiescence of latent HIV-1 provirus and give a molecular basis to the reported efficacy of combination therapy of conventional anti-HIV drugs with an HDAC inhibitor in accelerating the clearance of HIV-1 from individuals infected with the virus.

Links

PubMed Online version:10.1074/jbc.M511773200

Keywords

Antiviral Agents/pharmacology; Chromatin/metabolism; DNA-Binding Proteins/metabolism; DNA-Binding Proteins/physiology; Gene Expression Regulation, Viral; HIV/metabolism; HIV Core Protein p24/chemistry; HL-60 Cells; Histone Deacetylase 1; Histone Deacetylases/metabolism; Histones/metabolism; Humans; Promoter Regions, Genetic; Terminal Repeat Sequences; Transcription Factors/metabolism; Transcription Factors/physiology; Transcription, Genetic; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TBP

enables

GO:0000976: transcription regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TFAP4

enables

GO:0042826: histone deacetylase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13547

F

Seeded From UniProt

complete

HUMAN:TFAP4

enables

GO:0000976: transcription regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TFAP4

involved_in

GO:0043922: negative regulation by host of viral transcription

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TFAP4

involved_in

GO:0043392: negative regulation of DNA binding

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HDAC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q01664

F

Seeded From UniProt

complete

HUMAN:TBP

enables

GO:0044212: transcription regulatory region DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:HDAC1

involved_in

GO:0043922: negative regulation by host of viral transcription

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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