LIM protein Ajuba functions as a nuclear receptor corepressor and negatively regulates retinoic acid signaling

Zhaoyuan Hou, Hongzhuang Peng, David E. White, Dmitri G. Negorev, Gerd G. Maul, Yunfeng Feng, Gregory D. Longmore, Samuel Waxman, Arthur Z Zelent, Frank J. Rauscher

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Corepressors play an essential role in nuclear receptor-mediated transcriptional repression. In general, corepressors directly bind to nuclear receptors via CoRNR boxes (L/I-X-X-I/V-I) in the absence of ligand and appear to act as scaffolds to further recruit chromatin remodeling complexes to specific target genes. Here,we describe the identification of the multiple LIM domain protein Ajuba as a unique corepressor for a subset of nuclear hormone receptors. Ajuba contains functional nuclear-receptor interacting motifs and selectively interacts with retinoic acid receptors (RARs) and rexinoid receptor (RXRs) subtypes in a ligand-dependent manner. Simultaneous mutation of thesemotifs abolishes RAR binding and concomitantly leads to loss of repression on RARE reporter genes. P19 cells depleted of Ajuba are highly sensitizedtoall-trans retinoic acid(atRA)-inducedtranscription and differentiation. In the absence of atRA, Ajuba can be readily found at the RARE control elements of RAR endogenous target genes. Stimulation of cells with at RA results in the dissociation of Ajuba from these regions. Moreover, we observed that coexpression of the known Ajuba binding partner Prmt5 (protein arginine methyltransferase-5) inhibited the Ajuba/RAR interaction. The high-affinity Ajuba-RAR/RXR interaction site overlaps the region responsible for Ajuba/Prmt5 binding, and thus binding appears to bemutually exclusive, providing a potential mechanism for these observations. Identification of Ajuba as a unique corepressor for nuclear receptors sheds new light on mechanisms for nuclear receptor-mediated repression and provides a unique target for developing more effective therapeutics to modulate this important pathway.

Original languageEnglish (US)
Pages (from-to)2938-2943
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number7
DOIs
StatePublished - Feb 16 2010
Externally publishedYes

Fingerprint

Co-Repressor Proteins
Retinoic Acid Receptors
Cytoplasmic and Nuclear Receptors
Tretinoin
Protein-Arginine N-Methyltransferases
Proteins
LIM Domain Proteins
Ligands
Chromatin Assembly and Disassembly
Reporter Genes
Genes
Carrier Proteins
Mutation

Keywords

  • Differentiation
  • Hox genes
  • LIM domain
  • Retinoic acid receptors

ASJC Scopus subject areas

  • General

Cite this

LIM protein Ajuba functions as a nuclear receptor corepressor and negatively regulates retinoic acid signaling. / Hou, Zhaoyuan; Peng, Hongzhuang; White, David E.; Negorev, Dmitri G.; Maul, Gerd G.; Feng, Yunfeng; Longmore, Gregory D.; Waxman, Samuel; Zelent, Arthur Z; Rauscher, Frank J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 7, 16.02.2010, p. 2938-2943.

Research output: Contribution to journalArticle

Hou, Z, Peng, H, White, DE, Negorev, DG, Maul, GG, Feng, Y, Longmore, GD, Waxman, S, Zelent, AZ & Rauscher, FJ 2010, 'LIM protein Ajuba functions as a nuclear receptor corepressor and negatively regulates retinoic acid signaling', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 7, pp. 2938-2943. https://doi.org/10.1073/pnas.0908656107
Hou, Zhaoyuan ; Peng, Hongzhuang ; White, David E. ; Negorev, Dmitri G. ; Maul, Gerd G. ; Feng, Yunfeng ; Longmore, Gregory D. ; Waxman, Samuel ; Zelent, Arthur Z ; Rauscher, Frank J. / LIM protein Ajuba functions as a nuclear receptor corepressor and negatively regulates retinoic acid signaling. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 7. pp. 2938-2943.
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AU - Hou, Zhaoyuan

AU - Peng, Hongzhuang

AU - White, David E.

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AU - Maul, Gerd G.

AU - Feng, Yunfeng

AU - Longmore, Gregory D.

AU - Waxman, Samuel

AU - Zelent, Arthur Z

AU - Rauscher, Frank J.

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