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* Institut für Physiologische Chemie I, Heinrich-Heine-Universität, D-40001 Düsseldorf, Germany;
Genetisches Institut der Justus-Liebig-Universität, D-35392 Giessen, Germany; and
Georg-Speyer-Haus, D-60596 Frankfurt, Germany
2Correspondence: Institut für Physiologische Chemie I. Heinrich-Heine-Universität Düsseldorf, Postfach 10 10 07, D-40001 Düsseldorf, Germany. E-mail: carlberg{at}uni-duesseldorf.de
The vitamin D receptor (VDR) is a transcription factor that
transmits incoming 1,25-dihydroxyvitamin D3
(1
,25(OH)2D3) signaling via combined contact
with coactivator proteins and specific DNA binding sites (VDREs), which
ultimately results in activation of transcription. In contrast, the
mechanisms of transcriptional repression via the VDR are less well
understood. This study documents VDR-dependent transcriptional
repression largely via histone deacetylase (HDAC) activity. Direct,
ligand-sensitive protein-protein interaction of the VDR with the
nuclear receptor corepressor (NCoR) and a novel corepressor, called
Alien, was demonstrated to be comparable but independent of the VDR
AF-2 trans-activation domain. Functional assays
indicated that Alien, but not NCoR, displays selectivity for different
VDRE structures for transferring these repressive effects into gene
regulatory activities. Moreover, superrepression via Alien was found to
be affected only in part by HDAC inhibitors such as trichostatin A.
Finally, for a dissociation of VDR-Alien complexes in
vitro and in vivo, higher ligand concentrations
were needed than for a dissociation of VDR-NCoR complexes. This
suggests that Alien and NCoR are using different interfaces for
interaction with the VDR and different pathways for mediating
superrepression, which in turn characterizes Alien as a representative
of a new class of corepressors. Taken together, association of the VDR
with corepressor proteins provides a further level of transcriptional
regulation, which is emerging as a complex network of protein-protein interaction-mediated control.—Polly, P., Herdick,
M., Moehren, U., Baniahmad, A., Heinzel, T., Carlberg, C. VDR-Alien: a
novel, DNA-selective vitamin D3 receptor-corepressor
partnership.
Key Words: gene regulation • repression • NCoR
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