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

Apr 12, 2002Oncogene

Retinoic acid that blocks AP-1 may target specific Jun or Fos protein pairs without reducing coactivators or AP-1 single units

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Abstract

Retinoic acid (RA) suppresses AP-1 activity in mouse epidermal JB6 cells exposed to TPA.

RA treatment inhibits TPA-induced AP-1 activation, which is necessary for the transformation of JB6 P+ cells.
Overexpression of AP-1 components did not restore TPA-induced AP-1 activation, suggesting a lack of direct interaction with RA.
The corepressor SMRT suppresses AP-1 activity, but does not mediate the transrepression effect of RA.
RA treatment does not prevent TPA-induced phosphorylation of ERK or expression of Jun/Fos proteins, indicating selective inhibition of AP-1 activity.
The transcriptional activities of full-length JunB and Fra-1 are increased by TPA but suppressed by RA, highlighting potential targets for RA's action.

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

Abstract

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