Organochlorine-mediated potentiation of the general coactivator p300 through p38 mitogen-activated protein kinase.
The activity of nuclear transcription factors is often regulated by specific kinase-signaling pathways. We have previously shown that the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) stimulates activator protein-1 activity through the p38 mitogen-activated protein kinase (MAPK). Here, we show that DDT and its metabolites also stimulate the transcriptional activity of cyclic adenosine monophosphate response element-binding protein and Elk1 and potentiate gene expression through cyclic adenosine monophosphate and hypoxia response elements. Because DDT stimulates gene expression through various transcription factors and hence multiple response elements, we hypothesized that p38 signaling targets a common shared transcriptional activator. Here, we demonstrate using both pharmacological and molecular techniques, the general coactivator p300 is phosphorylated and potentiated by the p38 MAPK signaling cascade. We further show that p38 directly phosphorylates p300 in its N-terminus. These results, together with our previous work, suggest that p38 stimulates downstream transcription factors in part by targeting the general coactivator p300.
Bratton
Melyssa R
MR
Department of Pharmacology, Tulane University Health Science Center, New Orleans, LA 70112, USA.
Frigo
Daniel E
DE
Vigh-Conrad
Katinka A
KA
Fan
Daju
D
Wadsworth
Scott
S
McLachlan
John A
JA
Burow
Matthew E
ME
D015153:Blotting, Western; D002460:Cell Line; D003634:DDT / Q000494:pharmacology*; D017930:Genes, Reporter; D006801:Humans; D020935:MAP Kinase Signaling System; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors / Q000187:drug effects* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D014157:Transcription Factors; D003634:DDT; D050880:p300-CBP Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases
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