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PMID: 12052862 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Retinoic acid receptors inhibit AP1 activation by regulating extracellular signal-regulated kinase and CBP recruitment to an AP1-responsive promoter.

Molecular and cellular biology ·Vol. 22 ·No. 13 ·2002-07-00 ·Pages 4522-34

Benkoussa M, Brand C, Delmotte MH, Formstecher P, Lefebvre P

Abstract

Retinoids exhibit antineoplastic activities that may be linked to retinoid receptor-mediated transrepression of activating protein 1 (AP1), a heterodimeric transcription factor composed of fos- and jun-related proteins. Here we show that transcriptional activation of an AP1-regulated gene through the mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) pathway (MAPK(ERK)) is characterized, in intact cells, by a switch from a fra2-junD dimer to a junD-fosB dimer loading on its promoter and by simultaneous recruitment of ERKs, CREB-binding protein (CBP), and RNA polymerase II. All-trans-retinoic acid (atRA) receptor (RAR) was tethered constitutively to the AP1 promoter. AP1 transrepression by retinoic acid was concomitant to glycogen synthase kinase 3 activation, negative regulation of junD hyperphosphorylation, and to decreased RNA polymerase II recruitment. Under these conditions, fra1 loading to the AP1 response element was strongly increased. Importantly, CBP and ERKs were excluded from the promoter in the presence of atRA. AP1 transrepression by retinoids was RAR and ligand dependent, but none of the functions required for RAR-mediated transactivation was necessary for AP1 transrepression. These results indicate that transrepressive effects of retinoids are mediated through a mechanism unrelated to transcriptional activation, involving the RAR-dependent control of transcription factors and cofactor assembly on AP1-regulated promoters.

MeSH Terms
Anisomycin/pharmacology CREB-Binding Protein Calcium-Calmodulin-Dependent Protein Kinases/drug effects,metabolism DNA/metabolism Dimerization Enzyme Inhibitors/pharmacology Glycogen Synthase Kinase 3 Glycogen Synthase Kinases HeLa Cells/drug effects,radiation effects Humans MAP Kinase Kinase 1 MAP Kinase Kinase 4 Mitogen-Activated Protein Kinase Kinases/drug effects,metabolism,radiation effects Mitogen-Activated Protein Kinases/antagonists & inhibitors,genetics,metabolism Mutation Nuclear Proteins/genetics,metabolism Nuclear Receptor Co-Repressor 1 Promoter Regions, Genetic Protein Serine-Threonine Kinases/drug effects,metabolism,radiation effects Receptors, Retinoic Acid/drug effects,genetics,metabolism Repressor Proteins/genetics,metabolism Response Elements Retinoic Acid Receptor alpha Retinoid X Receptors Tetradecanoylphorbol Acetate/pharmacology Trans-Activators/genetics,metabolism Transcription Factor AP-1/drug effects,genetics,metabolism Transcription Factors/drug effects,genetics,metabolism Tretinoin/pharmacology Ultraviolet Rays
Chemicals
Enzyme Inhibitors NCOR1 protein, human Nuclear Proteins Nuclear Receptor Co-Repressor 1 RARA protein, human Receptors, Retinoic Acid Repressor Proteins Retinoic Acid Receptor alpha Retinoid X Receptors Trans-Activators Transcription Factor AP-1 Transcription Factors Tretinoin Anisomycin DNA CREB-Binding Protein CREBBP protein, human Glycogen Synthase Kinases Protein Serine-Threonine Kinases Calcium-Calmodulin-Dependent Protein Kinases Mitogen-Activated Protein Kinases Glycogen Synthase Kinase 3 MAP Kinase Kinase 1 MAP Kinase Kinase 4 MAP2K1 protein, human MAP2K4 protein, human Mitogen-Activated Protein Kinase Kinases Tetradecanoylphorbol Acetate
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Benkoussa Madjid
INSERM U 459 and Ligue Nationale Contre le Cancer, Faculté de Médecine Henri Warembourg, 59045 Lille Cedex, France.
Brand Céline
Delmotte Marie-Hélène
Formstecher Pierre
Lefebvre Philippe
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.22.13.4522-4534.2002
Published
2002-07-00
Pages
4522-34
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC133906
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.22.13.4522-4534.2002 PMC Full Text View journal details
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