title: AP-1 transrepressing retinoic acid does not deplete coactivators or AP-1 monomers but may target specific Jun or Fos containing dimers.
abstract: Retinoic acid (RA) inhibits tumor promotion in many models in vivo and in vitro, among them mouse epidermal JB6 cells. RA treatment suppresses 12-O-tetradecanoylphorbol-13-acetate (TPA) induced AP-1 activity, an activity that is required for transformation of JB6 P+ cells. The molecular mechanism of AP-1 transrepression by retinoids is unclear, especially as related to inhibition of transformation. Overexpression of AP-1 components did not rescue TPA induced AP-1 activation nor did a GST pull down experiment implicate direct binding, thus rendering unlikely both a Jun/Fos-RA-RAR direct interaction and a Jun/Fos sequestration mechanism. Overexpression of p300, SRC-1 or pCAF did not abrogate AP-1 suppression by RA, thus arguing against coactivator competition. Overexpression of the corepressor silencing mediator for retinoic acid and thyroid hormone receptors (SMRT) suppressed AP-1 activity. However, SMRT but not RA inhibited cJun transactivation, suggesting SMRT does not mediate RA transrepression. RA treatment also did not block TPA induced ERK phosphorylation, Jun/Fos family protein expression except for cFos, or DNA binding of the AP-1 complex. The transcriptional activities of full-length JunB and full-length Fra-1, but not the transactivation domain fusions, were increased by TPA treatment and suppressed by RA. Since these full-length fusions have bzip domains, the results suggest that JunB and/or Fra-1-containing dimers may constitute one target of RA for transrepression of AP-1.
authors.affiliation: Gene Regulation Section, Basic Research Laboratory, National Cancer Institute at Frederick, Frederick, Maryland 21702-1201, USA.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Suzukawa
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Colburn
mesh_terms: D000818:Animals; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D051921:Fos-Related Antigen-2; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D056985:Nuclear Receptor Co-Repressor 2; D011485:Protein Binding / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D000099169:Fos-Related Antigen 1
chemical_list: D004247:DNA; D004268:DNA-Binding Proteins; D051921:Fos-Related Antigen-2; D020928:Mitogen-Activated Protein Kinases; D056985:Nuclear Receptor Co-Repressor 2; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012097:Repressor Proteins; D013755:Tetradecanoylphorbol Acetate; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014212:Tretinoin; D000099169:Fos-Related Antigen 1; C497873:Fosl2 protein, mouse; C539131:Ncor2 protein, mouse