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  • The EMBO Journal (2004) 23, 1598 - 1608
  • doi:10.1038/sj.emboj.7600157

Published online: 25 March 2004

Transrepression by a liganded nuclear receptor via a bHLH activator through co-regulator switching

Akiko Murayama1,2,a, Mi-sun Kim1,a, Junn Yanagisawa1,2, Ken-ichi Takeyama1,3 and Shigeaki Kato1,3

  1. Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
  2. Institute of Applied Biochemistry, University of Tsukuba, Tenno-dai, Tsukuba Science City, Ibaraki, Japan
  3. SORST, Japan Science and Technology, Honcho, Kawaguchi, Saitama, Japan

Correspondence to:

Shigeaki Kato, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Tel.: +81 3 5841 7890; Fax: +81 3 5841 8477; E-mail: uskato@mail.ecc.u-tokyo.ac.jp

aThese authors contributed equally to this work

Received 14 October 2003; Accepted 13 February 2004

Vitamin D receptor (VDR) is essential for ligand-induced gene repression of 25(OH)D3 1alpha-hydroxylase (1alpha(OH)ase) in mammalian kidney, while this gene expression is activated by protein kinase A (PKA) signaling downstream of the parathyroid hormone action. The mapped negative vitamin D response element (1alphanVDRE) in the human 1alpha(OH)ase gene promoter (around 530 bp) was distinct from those of the reported DR3-like nVDREs, composed of two E-box-like motifs. Unlike the reported nVDREs, no direct binding of VDR/RXR heterodimer to 1alphanVDRE was detected. A bHLH-type factor, designated VDIR, was identified as a direct sequence-specific activator of 1alphanVDRE. The transactivation function of VDIR was further potentiated by activated-PKA signaling through phosphorylation of serine residues in the transactivation domains, with the recruitment of a p300 histone acetyltransferase co-activator. The ligand-dependent association of VDR/RXR heterodimer with VDIR bound to 1alphanVDRE caused the dissociation of p300 co-activators from VDIR, and the association of HDAC co-repressor complex components resulting in ligand-induced transrepression. Thus, the present study deciphers a novel mechanism of ligand-induced transrepression by nuclear receptor via co-regulator switching.

  • Keywords:

    • bHLH-type activator,
    • co-regulator,
    • nuclear receptor,
    • transrepression,
    • vitamin D