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Essential role of p53 phosphorylation by p38 MAPK in apoptosis induction by the HIV-1 envelope
The proapoptotic activity of the transcription factor p53 critically depends on the phosphorylation of serine 46 (p53S46P). Here, we show that syncytia containing p53S46P could be detected in lymph node biopsies from human immunodeficiency virus (HIV)-1 carriers, in the brain of patients with HIV-1–...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2005
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2212781/ https://www.ncbi.nlm.nih.gov/pubmed/15642743 http://dx.doi.org/10.1084/jem.20041502 |
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author | Perfettini, Jean-Luc Castedo, Maria Nardacci, Roberta Ciccosanti, Fabiola Boya, Patricia Roumier, Thomas Larochette, Nathanael Piacentini, Mauro Kroemer, Guido |
author_facet | Perfettini, Jean-Luc Castedo, Maria Nardacci, Roberta Ciccosanti, Fabiola Boya, Patricia Roumier, Thomas Larochette, Nathanael Piacentini, Mauro Kroemer, Guido |
author_sort | Perfettini, Jean-Luc |
collection | PubMed |
description | The proapoptotic activity of the transcription factor p53 critically depends on the phosphorylation of serine 46 (p53S46P). Here, we show that syncytia containing p53S46P could be detected in lymph node biopsies from human immunodeficiency virus (HIV)-1 carriers, in the brain of patients with HIV-1–associated dementia and in cocultures of HeLa expressing the HIV-1 envelope glycoprotein complex (Env) with HeLa cells expressing CD4. In this latter model, cell death was the result of a sequential process involving cell fusion, nuclear fusion (karyogamy), phosphorylation of serine 15 (p53S15P), later on serine 46 (p53S46P), and transcription of p53 target genes. Cytoplasmic p38 mitogen-activated protein kinase (MAPK) was found to undergo an activating phosphorylation (p38T180/Y182P [p38 with phosphorylated threonine 180 and tyrosine 182]) before karyogamy and to translocate into karyogamic nuclei. p38T180/Y182P colocalized and coimmunoprecipitated with p53S46P. Recombinant p38 phosphorylated recombinant p53 on serine 46 in vitro. Inhibition of p38 MAPK by pharmacological inhibitors, dominant-negative p38, or small interfering RNA, suppressed p53S46P (but not p53S15P), the expression of p53-inducible genes, the conformational activation of proapoptotic Bax and Bak, the release of cytochrome c from mitochondria, and consequent apoptosis. p38T180/Y182P was also detected in HIV-1–induced syncytia, in vivo, in patients' lymph nodes and brains. Dominant-negative MKK3 or MKK6 inhibited syncytial activation of p38, p53S46P, and apoptosis. Altogether, these findings indicate that p38 MAPK-mediated p53 phosphorylation constitutes a critical step of Env-induced apoptosis. |
format | Text |
id | pubmed-2212781 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2005 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-22127812008-03-11 Essential role of p53 phosphorylation by p38 MAPK in apoptosis induction by the HIV-1 envelope Perfettini, Jean-Luc Castedo, Maria Nardacci, Roberta Ciccosanti, Fabiola Boya, Patricia Roumier, Thomas Larochette, Nathanael Piacentini, Mauro Kroemer, Guido J Exp Med Article The proapoptotic activity of the transcription factor p53 critically depends on the phosphorylation of serine 46 (p53S46P). Here, we show that syncytia containing p53S46P could be detected in lymph node biopsies from human immunodeficiency virus (HIV)-1 carriers, in the brain of patients with HIV-1–associated dementia and in cocultures of HeLa expressing the HIV-1 envelope glycoprotein complex (Env) with HeLa cells expressing CD4. In this latter model, cell death was the result of a sequential process involving cell fusion, nuclear fusion (karyogamy), phosphorylation of serine 15 (p53S15P), later on serine 46 (p53S46P), and transcription of p53 target genes. Cytoplasmic p38 mitogen-activated protein kinase (MAPK) was found to undergo an activating phosphorylation (p38T180/Y182P [p38 with phosphorylated threonine 180 and tyrosine 182]) before karyogamy and to translocate into karyogamic nuclei. p38T180/Y182P colocalized and coimmunoprecipitated with p53S46P. Recombinant p38 phosphorylated recombinant p53 on serine 46 in vitro. Inhibition of p38 MAPK by pharmacological inhibitors, dominant-negative p38, or small interfering RNA, suppressed p53S46P (but not p53S15P), the expression of p53-inducible genes, the conformational activation of proapoptotic Bax and Bak, the release of cytochrome c from mitochondria, and consequent apoptosis. p38T180/Y182P was also detected in HIV-1–induced syncytia, in vivo, in patients' lymph nodes and brains. Dominant-negative MKK3 or MKK6 inhibited syncytial activation of p38, p53S46P, and apoptosis. Altogether, these findings indicate that p38 MAPK-mediated p53 phosphorylation constitutes a critical step of Env-induced apoptosis. The Rockefeller University Press 2005-01-17 /pmc/articles/PMC2212781/ /pubmed/15642743 http://dx.doi.org/10.1084/jem.20041502 Text en Copyright © 2005, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Perfettini, Jean-Luc Castedo, Maria Nardacci, Roberta Ciccosanti, Fabiola Boya, Patricia Roumier, Thomas Larochette, Nathanael Piacentini, Mauro Kroemer, Guido Essential role of p53 phosphorylation by p38 MAPK in apoptosis induction by the HIV-1 envelope |
title | Essential role of p53 phosphorylation by p38 MAPK in apoptosis induction by the HIV-1 envelope |
title_full | Essential role of p53 phosphorylation by p38 MAPK in apoptosis induction by the HIV-1 envelope |
title_fullStr | Essential role of p53 phosphorylation by p38 MAPK in apoptosis induction by the HIV-1 envelope |
title_full_unstemmed | Essential role of p53 phosphorylation by p38 MAPK in apoptosis induction by the HIV-1 envelope |
title_short | Essential role of p53 phosphorylation by p38 MAPK in apoptosis induction by the HIV-1 envelope |
title_sort | essential role of p53 phosphorylation by p38 mapk in apoptosis induction by the hiv-1 envelope |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2212781/ https://www.ncbi.nlm.nih.gov/pubmed/15642743 http://dx.doi.org/10.1084/jem.20041502 |
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