Abstract
Histone deacetylase inhibitors (HDACi) induce growth arrest and differentiation, particularly in the colon where they are potential chemotherapeutic agents. A key mediator of HDACi action is the cyclin dependent kinase (CDK) inhibitor p21(waf1). HDACi treatment of colonic cells promotes the formation of an ATM/ZBP-89/p300 complex on p21(waf1) proximal promoter, and this multi-molecular complex plays an important role in HDACi induction of p21(waf1) expression in vitro and mucosal protection in vivo. Here we found that ZBP-89 is phosphorylated by ATM kinase in vitro and in vivo. Disruption of the ATM phosphorylation motif (202)SQ within the zinc finger domain of ZBP-89 attenuated its ability to enhance p21(waf1) activation by butyrate. Moreover, disruption of the ATM phosphorylation site abrogated the ability of ZBP-89 to potentiate butyrate induction of endogenous p21(waf1) expression. These results demonstrate that ATM phosphorylation of ZBP-89 contributes to HDACi induction of p21(waf1) gene expression.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Ataxia Telangiectasia Mutated Proteins
-
Butyrates / pharmacology*
-
Cell Cycle Proteins / genetics
-
Cell Cycle Proteins / metabolism*
-
Cell Line
-
Cyclin-Dependent Kinase Inhibitor p21 / genetics
-
Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism*
-
Gene Expression Regulation / drug effects
-
Humans
-
Hydroxamic Acids / pharmacology
-
Phosphoserine / metabolism
-
Protein Serine-Threonine Kinases / genetics
-
Protein Serine-Threonine Kinases / metabolism*
-
Transcription Factors / genetics
-
Transcription Factors / metabolism*
-
Tumor Suppressor Protein p53 / metabolism
-
Tumor Suppressor Proteins / genetics
-
Tumor Suppressor Proteins / metabolism*
Substances
-
Butyrates
-
CDKN1A protein, human
-
Cell Cycle Proteins
-
Cyclin-Dependent Kinase Inhibitor p21
-
DNA-Binding Proteins
-
Hydroxamic Acids
-
Transcription Factors
-
Tumor Suppressor Protein p53
-
Tumor Suppressor Proteins
-
ZNF148 protein, human
-
Zfp148 protein, mouse
-
Zfp148 protein, rat
-
Phosphoserine
-
trichostatin A
-
ATM protein, human
-
Ataxia Telangiectasia Mutated Proteins
-
Atm protein, mouse
-
Protein Serine-Threonine Kinases