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PMID: 18397884 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Regulation of TIP60 by ATF2 modulates ATM activation.

The Journal of biological chemistry ·Vol. 283 ·No. 25 ·2008-06-20 ·Pages 17605-14

Bhoumik A, Singha N, O'Connell MJ, Ronai ZA

Abstract

TIP60 (HTATIP) is a histone acetyltransferase (HAT) whose function is critical in regulating ataxia-telangiectasia mutated (ATM) activation, gene expression, and chromatin acetylation in DNA repair. Here we show that under non-stressed conditions, activating transcription factor-2 (ATF2) in cooperation with Cul3 ubiquitin ligase promotes degradation of TIP60, thereby attenuating its HAT activity. Inhibiting either ATF2 or Cul3 expression by small interfering RNA stabilizes the TIP60 protein. ATF2 association with TIP60 on chromatin is decreased following exposure to ionizing radiation (IR), resulting in enhanced TIP60 stability and activity. We also identified a panel of melanoma and prostate cancer cell lines whose ATF2 expression is inversely correlated with TIP60 levels and ATM activation after IR. Inhibition of ATF2 expression in these lines restored TIP60 protein levels and both basal and IR-induced levels of ATM activity. Our study provides novel insight into regulation of ATM activation by ATF2-dependent control of TIP60 stability and activity.

MeSH Terms
Activating Transcription Factor 2/metabolism Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins/metabolism Cell Line, Tumor Chromatin/metabolism Cullin Proteins/metabolism DNA Damage DNA-Binding Proteins/metabolism Gene Expression Regulation Gene Expression Regulation, Neoplastic HeLa Cells Histone Acetyltransferases/chemistry,metabolism Humans Lysine Acetyltransferase 5 Models, Biological Models, Genetic Protein Binding Protein Serine-Threonine Kinases/metabolism RNA Interference Tumor Suppressor Proteins/metabolism
Chemicals
ATF2 protein, human Activating Transcription Factor 2 CUL3 protein, human Cell Cycle Proteins Chromatin Cullin Proteins DNA-Binding Proteins Tumor Suppressor Proteins Histone Acetyltransferases KAT5 protein, human Lysine Acetyltransferase 5 ATM protein, human Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Bhoumik Anindita
Signal Transduction Program, Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Singha Netai
O'Connell Matthew J
Ronai Ze'ev A
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M802030200
Published
2008-06-20
Epub
2008-00-08
Pages
17605-14
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2427333
Subset
IM
Grants
NCI NIH HHS · CA 099961 · United States
NCI NIH HHS · CA100076 · United States
External Links
PubMed source DOI: 10.1074/jbc.M802030200 PMC Full Text View journal details
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