Silencing Mediator of Retinoid and Thyroid Hormone Receptors and Activating Signal Cointegrator-2 as Transcriptional Coregulators of the Orphan Nuclear Receptor Nur77

Young Chang Sohn,Eunyee Kwak,Yeonja Na,Jae Woon Lee,Soo-Kyung Lee

doi:10.1074/jbc.m107208200

Young Chang Sohn, Eunyee Kwak + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m107208200

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Abstract

For the orphan nuclear receptor subfamily that includes Nur77 (NGFI-B), Nurr1, and NOR-1, no transcriptional coregulators have been identified thus far. In this report, we found that Ca(2+)/calmodulin-dependent protein kinase IV enhances Nur77 transactivation in cotransfections either alone or in synergy with AF2dependent coactivator ASC-2, whereas corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) is repressive. Interestingly, Nur77 interacted with SMRT but did not directly bind ASC-2, and accordingly, the putative AF2 core domain of Nur77 did not affect the Nur77 transactivation. SMRT harbors transferable repression domains that associate with various histone deacetylases. Surprisingly, histone deacetylase inhibitor trichostatin A was unable to block the repressive effect of SMRT while dramatically stimulating the Nur77 transactivation. These results suggest that SMRT and ASC-2 are specific coregulators of Nur77 and that SMRT may dynamically compete with a putative adaptor molecule, which links ASC-2 to Nur77, for the identical binding sites within Nur77 in vivo.

Highlights

The nuclear receptor superfamily is a group of ligand-dependent transcriptional regulatory proteins that function by binding to specific DNA sequences named hormone response elements in the promoters of target genes
CaMKIV is present in the nucleus of the cells in which it is expressed and has been implicated in the regulation of transcription of a number of genes including those encoding interleukin-2, members of the immediate early gene family such as c-fos; tumor necrosis family members such as CD40L, Fas ligand, and tumor necrosis factor; the neurotrophin brain-derived neurotrophic factor (BDNF); an EpsteinBarr virus gene involved in the switch to the lytic cycle called BZLF1; and orphan members of the steroid receptor superfamily such as retinoid-related orphan receptor (ROR) and chicken ovalbumin upstream transcription factor (COUP-TF) [15]
The only direct substrates for CaMKIV involved in transcription that have been defined to date are cAMP-response element-binding protein (CREB), cAMP response element modulator (CREM), and the NF␬B component p65 (16 –18), CBP has been indirectly implicated as a possible substrate [19]

Summary

Introduction

The nuclear receptor superfamily is a group of ligand-dependent transcriptional regulatory proteins that function by binding to specific DNA sequences named hormone response elements in the promoters of target genes (for a review, see Ref. 1). We found that Ca2؉/calmodulin-dependent protein kinase IV enhances Nur77 transactivation in cotransfections either alone or in synergy with AF2dependent coactivator ASC-2, whereas corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) is repressive.

Results

Conclusion