Human T-cell leukemia virus type-1-encoded protein HBZ represses p53 function by inhibiting the acetyltransferase activity of p300/CBP and HBO1
| Autor: | Amanda W. Rushing, John A. Ankney, Diana Grace Wright, Nicholas Polakowski, Isabelle Lemasson, Claire Marchal, Stephanie T. Nguyen, Kimson Hoang, Benoit Miotto |
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| Přispěvatelé: | Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Centre épigénétique et destin cellulaire ( EDC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Biochemistry and Biophysics [Chapel Hill], The University of North Carolina at Chapel Hill, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), East Carolina University [Greenville] (ECU), University of North Carolina System (UNC)-University of North Carolina System (UNC), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), University of North Carolina [Chapel Hill] (UNC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Department of Microbiology and Immunology [Greenville, SC, USA] (Brody School of Medicine), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the National Institutes of Health grant [CA128800 to I.L]. BM is supported by CNRS, Ligue contre le Cancer (Comité de Paris), Marie Curie International Reintegration Grant (PIRG07–2010–268448) and Laboratory of excellence 'Who am I?'. CM is a recipient of a fellowship from 'Ministère de l’Enseignement Supérieur, de la Recherche et des Technologies' (MESRT) and from 'Fondation pour la Recherche Médicale' (FDT20150532354)., Miotto, Benoit, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
p53 adult T-cell leukemia viruses Retroviridae Proteins Cell Cycle Proteins P300-CBP Transcription Factors medicine.disease_cause HBZ p300-CBP Transcription Factors Nuclear protein Etoposide Histone Acetyltransferases Human T-lymphotropic virus 1 [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology biology Reverse Transcriptase Polymerase Chain Reaction Nuclear Proteins Acetylation Provirus 3. Good health G2 Phase Cell Cycle Checkpoints Gene Expression Regulation Neoplastic Basic-Leucine Zipper Transcription Factors Oncology GADD45A Protein Binding Research Paper Cyclin-Dependent Kinase Inhibitor p21 histone acetyl transferase activity Viral protein Blotting Western 03 medical and health sciences Cell Line Tumor Coactivator [SDV.BBM] Life Sciences [q-bio]/Biochemistry Molecular Biology medicine Animals Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry Molecular Biology human T-cell leukemia virus type-1 Histone acetyltransferase biology.organism_classification HCT116 Cells Virology Molecular biology 030104 developmental biology HEK293 Cells biology.protein Tumor Suppressor Protein p53 [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology HeLa Cells |
| Zdroj: | Oncotarget Oncotarget, Impact journals, 2016 Oncotarget, Impact journals, 2016, 7 (2), pp.1687-706. ⟨10.18632/oncotarget.6424⟩ Oncotarget, 2016, 7 (2), pp.1687-706. ⟨10.18632/oncotarget.6424⟩ |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.6424⟩ |
| Popis: | International audience; Keywords: human T-cell leukemia virus type-1, adult T-cell leukemia, HBZ, histone acetyl transferase activity, p53 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. INTRODUCTION The tumor suppressor, p53, is a central regulator of genome stability in mammalian cells. Following DNA damage, p53 becomes acetylated and phosphorylated at multiple sites, thereby shifting the protein from an unstable, latent form to one that is stable, active and concentrated in the nucleus [1]. This transition allows p53 to bind to promoters of genes involved in cell cycle arrest, such as p21/CDKN1A and GADD45A, and activate their transcription [2–4]. p53 is also able to regulate expression of genes involved in the DNA damage response, apoptosis and in its own regulation [5, 6]. Although certain posttranslational modifications may serve redundant functions, there appears to be separate patterns of acetylation and phosphorylation of p53 that favor either cell cycle arrest and DNA repair or, alternatively, apoptosis [6]. Regardless of these complexities, it is clear that acetylation of p53 is essential in promoting either of the two cellular fates [7]. In general, acetylation has been shown to augment the transcriptional activity and stability of p53. For example, acetylation of lysine residues within the C-terminal domain of the protein have been found |
| Databáze: | OpenAIRE |
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