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AP-1 transrepressing retinoic acid does not deplete coactivators or AP-1 monomers but may target specific Jun or Fos containing dimers

Oncogene volume 21, pages 2181–2190 (2002)Cite this article

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.

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Acknowledgements

We are grateful to P Chambon, S Agarwal, Y Nakatani, L Feltzien, T Bowden, R Evans and M Lazar for kindly providing constructs, and to Matthew Young for valuable discussions. Kazumi Suzukawa was supported by a Japan Society for Promotion of Science Fellowship for Japanese Biomedical and Behavioral Researchers at NIH.

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  1. Gene Regulation Section, Basic Research Laboratory, National Cancer Institute at Frederick, Frederick, Maryland, 21702-1201, MD, USA

    Kazumi Suzukawa & Nancy H Colburn

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  1. Kazumi Suzukawa
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  2. Nancy H Colburn
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Correspondence to Nancy H Colburn.

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Suzukawa, K., Colburn, N. AP-1 transrepressing retinoic acid does not deplete coactivators or AP-1 monomers but may target specific Jun or Fos containing dimers. Oncogene 21, 2181–2190 (2002). https://doi.org/10.1038/sj.onc.1205281

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