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J Biol Chem, Vol. 274, Issue 19, 13503-13510, May 7, 1999
From the Instituto de Investigaciones Biomédicas, Consejo
Superior de Investigaciones Científicas and Universidad
Autónoma de Madrid, 28029 Madrid, Spain
Mutant K246A in the predicted helix 3 of the
ligand-binding domain, as well as mutants L417S and E420Q in helix 12, which contains the core ligand-dependent transcriptional
activation domain (AF-2), were generated to examine AF-2 activity of
the vitamin D receptor (VDR). These mutations abolished vitamin
D-dependent transactivation. In addition, VDR mediates a
ligand-dependent repression of the response of the retinoic
acid receptor
Lysine 246 of the Vitamin D Receptor Is Crucial for
Ligand-dependent Interaction with Coactivators and
Transcriptional Activity
2 promoter to retinoic acid, and the helix 3 and helix
12 mutants were unable to mediate transrepression. Furthermore, the VDR
mutants, but not the native receptor, enhanced phorbol ester induction
of the activator protein-1-containing collagenase promoter. The helix 3 and helix 12 mutations strikingly reduced the ability of VDR to
interact with the coactivators steroid receptor coactivator-1, ACTR,
and the CREB-binding protein. As a consequence, overexpression of
steroid receptor coactivator-1 increased vitamin
D-dependent transactivation by VDR but not by the K246A
mutant. These results indicate that the lysine 246 participates,
together with residues in helix 12, in the recruitment of coactivators
and that AF-2 activity is involved both in ligand-dependent
transactivation and in transrepression by VDR.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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