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Selective interaction of vitamin D receptor with transcriptional coactivators by a vitamin D analog
K Takeyama1, Y Masuhiro, H Fuse
1Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113, Japan.
Abstract:
The nuclear vitamin D receptor (VDR) is a member of a nuclear receptor superfamily and acts as a ligand-dependent transcription factor. A family of cotranscriptional activators (SRC-1, TIF2, and AIB-1) interacts with and activates the transactivation function of nuclear receptors in a ligand-dependent way. We examined interaction of VDR with these coactivators that was induced by several vitamin D analogs, since they exert differential subsets of the biological action of vitamin D through unknown mechanisms. Unlike other vitamin D analogs tested, OCT (22-oxa-1alpha,25-dihydroxyvitamin D3) induced interaction of VDR with TIF2 but not with SRC-1 or AIB-1. Consistent with these interactions, only TIF2 was able to potentiate the transactivation function of VDR bound to OCT. Thus, the present findings suggest that the structure of VDR is altered in a vitamin D analog-specific way, resulting in selective interactions of VDR with coactivators. Such selective interaction of coactivators with VDR may specify the array of biological actions of a vitamin D analog like OCT, possibly through activating a particular set of target gene promoters.
Insights
Vitamin D receptor (VDR) interactions with coactivators are specific to the vitamin D analog used. OCT selectively binds TIF2, influencing VDR
Area of Science:
- Molecular Endocrinology
- Nuclear Receptor Signaling
- Transcriptional Regulation
Background:
- The nuclear vitamin D receptor (VDR) is a ligand-dependent transcription factor.
- Cotranscriptional activators like SRC-1, TIF2, and AIB-1 modulate nuclear receptor activity.
- Vitamin D analogs have diverse biological actions mediated by unknown mechanisms.
Purpose of the Study:
- To investigate how different vitamin D analogs induce VDR interaction with coactivators.
- To understand the mechanism behind the selective biological actions of vitamin D analogs.
Main Methods:
- Studied VDR interactions with SRC-1, TIF2, and AIB-1.
- Utilized various vitamin D analogs, including OCT (22-oxa-1alpha,25-dihydroxyvitamin D3).
- Assessed the potentiation of VDR transactivation function by coactivators.
Main Results:
- OCT induced VDR interaction with TIF2 exclusively, unlike other analogs tested.
- Only TIF2 potentiated the transactivation function of VDR bound to OCT.
- VDR structure is altered specifically by vitamin D analogs, leading to selective coactivator interactions.
Conclusions:
- Selective coactivator interaction with VDR specifies the biological actions of vitamin D analogs like OCT.
- This selectivity may occur through the activation of specific target gene promoters.
- Findings provide insight into analog-specific VDR signaling pathways.