Page 42 - Vitamin D and Cancer

2 The Molecular Cancer Biology of the VDR 29

Other repressors appear to demonstrate more specific phenotypic specificity.
Hairless blocks VDR-mediated differentiation of keratinocytes, whereas addition
of 1a,25(OH) D displaces Hairless from the promoter of target genes and recruits
2 3
coactivators to promote differentiation [46–48]. Similarly, DREAM (downstream
regulatory element antagonist modulator) usually binds to direct repeat response
elements in the promoters of target genes to enhance transcription in VDR and
RAR target genes, in a calcium-dependent manner, and suggests that specificity
arises from the interactions of VDR with further tissue-specific cofactors [49].
Finally, the Williams syndrome transcription factor (WSTF), contained within
WINAC complex, identified by Kato and colleagues, directly interacts with unli-
ganded VDR and mediates binding to promoter sequences and can then bind and
recruit other co-regulatory proteins. WINAC has ATP-dependent chromatin-remod-
eling activity and contains both SWI/SNF components and DNA replication-related
factors. WINAC mediates the recruitment of unliganded VDR to its promoter target
sites, and may organize local nucleosomal positioning to allow promoters access to
co-regulators. This suggests a novel mechanism in transcriptional regulation, in
which VDR binds to gene promoters before ligand is present [50, 51].
A similar level of coactivator specificity is also beginning to emerge. Members
of the TRAP/DRIP complex were identified independently in association with the
VDR and other NRs including the GR [52, 53] and TR [54–56]. The exact specific-
ity of many of the co-regulatory factors remains to be established fully, although
there are some suggestions that certain co-activators are VDR-specific, for
example, NCoA-62 [57]. Similarly, knockout of TRAP220, which has multiple
NR interacting domains, has begun to reveal distinct interactions, and notably
disrupts the ability of the VDR to regulate hematopoietic differentiation [58, 59].
In keeping with the skin being a critical target for VDR actions, the specificity
of VDR interactions with cofactor complexes has been dissected in detail by
Bikle and colleagues who have demonstrated the timing and extent of coactivator
binding, and established a role for SRC3 during specific stages of keratinocyte
differentiation [60, 61].
Aside from the established co-regulators, some chaperone proteins have been
reported to be regulators of VDR-mediated transcription. HSP70 down-regulates
VDR to repress transcription [62], whereas BAG1L, an HSP70 binding protein, has
been shown to bind to the VDR, and enhances VDR-mediated transcription [63].
Similarly, p23 and HSP90 have been shown to release the VDR/coactivator com-
plex from the promoter of target genes in the presence of 1a,25(OH) D [64]. The
2 3
association of these HSPs suggests a natural cross-talk with other NRs, such as the
AR, that associate with these chaperones in the cytoplasm.
Posttranslational modifications (PTM) possibly confer further VDR specificity
of function. PTMs resulting from signal transduction processes, for example, bring
about phosphorylation, acetylation, and ubiquitinylation events on the AR [65]. The
VDR has been less extensively studied, but crucial roles have emerged for the phos-
phorylation of serine and threonine residues [66]. Subsequently, several residues
have been identified that appear to regulate DNA binding and cofactor recruitment.
The zinc finger DNA-binding domain is located at the N terminal of the VDR and