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PMID: 16436515 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation.

Molecular biology of the cell ·Vol. 17 ·No. 4 ·2006-04-00 ·Pages 1583-92

Moiseeva O, Mallette FA, Mukhopadhyay UK, Moores A, Ferbeyre G

Abstract

Interferons are cytokines with potent antiviral and antiproliferative activities. We report that although a transient exposure to beta-interferon induces a reversible cell cycle arrest, a sustained treatment triggers a p53-dependent senescence program. Beta-interferon switched on p53 in two steps. First, it induced the acetylation of p53 at lysine 320 and its dephosphorylation at serine 392 but not p53 activity. Later on, it triggered a DNA signaling pathway, the phosphorylation of p53 at serine 15 and its transcriptional activity. In agreement, beta-interferon-treated cells accumulated gamma-H2AX foci and phosphorylated forms of ATM and CHK2. The DNA damage signaling pathway was activated by an increase in reactive oxygen species (ROS) induced by interferon and was inhibited by the antioxidant N-acetyl cysteine. More important, RNA interference against ATM inhibited p53 phosphorylation at serine 15, p53 activity and senescence in response to beta-interferon. Beta-interferon-induced senescence was more efficient in cells expressing either, p53, or constitutive allele of ERK2 or RasV12. Hence, beta-interferon-induced senescence targets preferentially cells with premalignant changes.

MeSH Terms
Acetylation Ataxia Telangiectasia Mutated Proteins Cell Cycle/drug effects Cell Cycle Proteins/genetics,metabolism Cellular Senescence Checkpoint Kinase 2 DNA Damage DNA-Binding Proteins/genetics,metabolism Fibroblasts/drug effects,metabolism Histones/analysis,metabolism Humans Interferon-beta/pharmacology Lysine/metabolism Mitogen-Activated Protein Kinase 1/metabolism Phosphorylation Protein Serine-Threonine Kinases/genetics,metabolism RNA Interference Reactive Oxygen Species/metabolism Serine/metabolism Signal Transduction Transcription, Genetic Tumor Suppressor Protein p53/genetics,metabolism Tumor Suppressor Proteins/genetics,metabolism
Chemicals
Cell Cycle Proteins DNA-Binding Proteins H2AX protein, human Histones Reactive Oxygen Species Tumor Suppressor Protein p53 Tumor Suppressor Proteins Serine Interferon-beta Checkpoint Kinase 2 ATM protein, human Ataxia Telangiectasia Mutated Proteins CHEK2 protein, human Protein Serine-Threonine Kinases Mitogen-Activated Protein Kinase 1 Lysine
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Moiseeva Olga
Département de Biochimie, Université de Montréal, Montréal, Québec H3C 3J7, Canada.
Mallette Frédérick A
Mukhopadhyay Utpal K
Moores Adrian
Ferbeyre Gerardo
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.e05-09-0858
Published
2006-04-00
Epub
2006-00-25
Pages
1583-92
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC1415317
Subset
IM
External Links
PubMed source DOI: 10.1091/mbc.e05-09-0858 PMC Full Text View journal details
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