Page 40 - Vitamin D and Cancer

2 The Molecular Cancer Biology of the VDR 27

signal transduction responses [5, 6]. This is a feature of several NRs, such as the
ERa, where the NR is cycled through caveolae at the cell membrane to initiate
signal transduction pathways [6, 7]. The contribution of these actions to the overall
functions of 1a,25(OH) D remains to be clarified fully. Interestingly, there is also
2 3
evidence for the VDR to be actively trafficked into the nucleus upon ligand activa-
tion, in tandem with the heterodimeric partner RXRs [8], each in association with
specific importins [9].
The majority of findings to date have addressed a nuclear function for the VDR
associated with transcription. Structurally, the VDR is uncommon, compared to
other NRs (NRs), as it does not contain an activation domain at its amino terminus
(AF1). In most other receptors, this is an important domain for activation, for
example, for autonomous ligand-independent AF function domain. The VDR
instead relies on a domain in the carboxy terminus (AF-2) for activation and other
domains for heterodimerization with RXR [10]. The VDR ligand-binding pocket
contains hydrophobic residues such as His-305 and -397 that are important in the
binding of 1a,25(OH) D . Ligand binding specifically requires interaction of the
2 3
hydroxyl group of the A ring at carbon 1 of 1a,25(OH) D , which is added by the
2 3
action of the 1a hydroxylase enzyme. The binding of ligand causes an LBD con-
formational change, which allows the C-terminal helix 12 of the AF2 domain to
reposition into an active conformation, exposing a docking surface for transcrip-
tional co-regulators [11–13]. This switch of conformation of the LBD in the pres-
ence of ligand is a common feature in all ligand-binding NRs, as is the capacity to
undergo receptor–cofactor interactions. Thus, both the unliganded and liganded
VDR associates with a large number of different proteins involved with transcrip-
tional suppression and activation, respectively.
When located within the nucleus and in the absence of ligand, the VDR exist in
an “apo” state associated with RXR and corepressors (e.g., NCOR1 and NCOR2/
SMRT) [14, 15] as part of large complexes (~2.0 MDa) [14, 16] and bound to RE
sequences. These complexes in turn actively recruit a range of enzymes that post-
translationally modify histone tails, for example, histone deacetylases (HDACs)
and methyltransferases, and thereby maintain a locally condensed chromatin struc-
ture around response element sequences [17–20]. Ligand binding induces a so-
called holo state, facilitating the association of the VDR-RXR dimer with
coactivator complexes. A large number of interacting coactivator proteins have
been described, which can be divided into multiple families including the p160
family, the non-p160 members, and members of the large “bridging” TRAP/DRIP/
ARC complex, which links the receptor complex to the co-integrators CBP/p300
and basal transcriptional machinery [21, 22].
The complex choreography of these events has recently emerged from the study of
the VDR [17, 23–28] and other NRs [29–32], and involves cyclical rounds of
promoter-specific complex assembly, gene transactivation, complex disassembly, and
proteosome-mediated receptor degradation coincident with corepressor binding and
silencing of transcription. This gives rise to the characteristic periodicity of NR tran-
scriptional activation and pulsatile mRNA and protein accumulation. However, the
periodicity of VDR-induced mRNA accumulation of target genes is not shared, but