Carcinogenesis Advance Access originally published online on September 12, 2008
Carcinogenesis 2009 30(1):106-113; doi:10.1093/carcin/bgn213
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Organochlorine-mediated potentiation of the general coactivator p300 through p38 mitogen-activated protein kinase
1 Department of Pharmacology
2 Center for Bioenvironmental Research
3 Molecular and Cellular Biology Program, Tulane University Health Science Center, New Orleans, LA 70112, USA
4 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
5 Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ 08869-0602, USA
6 Department of Medicine, Section of Hematology and Medical Oncology
7 Department of Surgery, Tulane University Health Science Center, New Orleans, LA 70112, USA
8 Present address: Department of Human Genetics, The University of Chicago, Chicago, IL 60637
* To whom correspondence should be addressed. Department of Medicine, Section of Hematology and Medical Oncology, Tulane University Health Sciences Center, 1430 Tulane Avenue SL-78, New Orleans, LA 70112, USA. Tel: +1 504 988 6688; Fax: +1 504 988 6215; Email: mburow{at}tulane.edu
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.
Abbreviations: AP-1, activator protein-1; CA-MKK, constitutively active mitogen-activated protein kinase kinase; cDNA, complementary DNA; CREB, cyclic adenosine monophosphate response element binding; DDT, dichlorodiphenyltrichloroethane; DMEM, Dulbecco’s modified Eagle’s medium; DMSO, dimethyl sulfoxide; DN, dominant negative; ER, estrogen receptor; ERK, extracellular-signal regulated kinase; FBS, fetal bovine serum; GST, glutathione S-transferase; HEK, human embryonic kidney; MAPK, mitogen-activated protein kinase; MPA, tetradecanoyl-13-phorbol acetate
These authors contributed equally to this work and should both be considered first authors. Received July 21, 2008; revised August 28, 2008; accepted September 1, 2008.
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