title: Human T-cell leukemia virus type-1-encoded protein HBZ represses p53 function by inhibiting the acetyltransferase activity of p300/CBP and HBO1.
abstract: Adult T-cell leukemia (ATL) is an often fatal malignancy caused by infection with the complex retrovirus, human T-cell Leukemia Virus, type 1 (HTLV-1). In ATL patient samples, the tumor suppressor, p53, is infrequently mutated; however, it has been shown to be inactivated by the viral protein, Tax. Here, we show that another HTLV-1 protein, HBZ, represses p53 activity. In HCT116 p53+/+ cells treated with the DNA-damaging agent, etoposide, HBZ reduced p53-mediated activation of p21/CDKN1A and GADD45A expression, which was associated with a delay in G2 phase-arrest. These effects were attributed to direct inhibition of the histone acetyltransferase (HAT) activity of p300/CBP by HBZ, causing a reduction in p53 acetylation, which has be linked to decreased p53 activity. In addition, HBZ bound to, and inhibited the HAT activity of HBO1. Although HBO1 did not acetylate p53, it acted as a coactivator for p53 at the p21/CDKN1A promoter. Therefore, through interactions with two separate HAT proteins, HBZ impairs the ability of p53 to activate transcription. This mechanism may explain how p53 activity is restricted in ATL cells that do not express Tax due to modifications of the HTLV-1 provirus, which accounts for a majority of patient samples.
authors.affiliation: Brody School of Medicine, Department of Microbiology and Immunology, East Carolina University, Greenville, NC, USA.
authors.forename: Diana G
authors.initials: DG
authors.lastname: Wright
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216, CNRS, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Marchal
authors.affiliation: Brody School of Medicine, Department of Microbiology and Immunology, East Carolina University, Greenville, NC, USA.
authors.forename: Kimson
authors.initials: K
authors.lastname: Hoang
authors.affiliation: Brody School of Medicine, Department of Microbiology and Immunology, East Carolina University, Greenville, NC, USA.|Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Ankney
authors.affiliation: Brody School of Medicine, Department of Microbiology and Immunology, East Carolina University, Greenville, NC, USA.
authors.forename: Stephanie T
authors.initials: ST
authors.lastname: Nguyen
authors.affiliation: Brody School of Medicine, Department of Microbiology and Immunology, East Carolina University, Greenville, NC, USA.
authors.forename: Amanda W
authors.initials: AW
authors.lastname: Rushing
authors.affiliation: Brody School of Medicine, Department of Microbiology and Immunology, East Carolina University, Greenville, NC, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Polakowski
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216, CNRS, Paris, France.|INSERM, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Miotto
authors.affiliation: Brody School of Medicine, Department of Microbiology and Immunology, East Carolina University, Greenville, NC, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lemasson
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D012191:Retroviridae Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005047:Etoposide; D051548:Histone Acetyltransferases; D009687:Nuclear Proteins; D012191:Retroviridae Proteins; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C479751:HBZ protein, human T-cell leukemia virus type I; C496553:KAT7 protein, human
keywords: HBZ; adult T-cell leukemia; histone acetyl transferase activity; human T-cell leukemia virus type-1; p53