ATM phosphorylates ZBP-89 at Ser202 to potentiate p21waf1 induction by butyrate.
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.
Bai
Longchuan
L
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Merchant
Juanita L
JL
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002087:Butyrates / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D010768:Phosphoserine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D002087:Butyrates; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D006877:Hydroxamic Acids; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C110951:ZNF148 protein, human; C491741:Zfp148 protein, mouse; C491740:Zfp148 protein, rat; D010768:Phosphoserine; C012589:trichostatin A; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases