Page 41 - Vitamin D and Cancer

28 J. Thorne and M.J. Campbell

rather tends toward patterns that are specific for individual target genes and suggests that
promoter-specific complexes combine to determine the precise periodicity [23, 24].

2.1.2 VDR Signal Specificity

Historically, researchers have tended to consider transcription factor actions in a
somewhat monochrome view, for example, as illustrated for MYC and AP-1. These
views are currently being revised in the light of surveys of genome binding sites
and dissection of biological actions in a broader context (for example, reviewed in
[33, 34]). These findings suggest that the functions of a given transcription factor
superfamily are distilled through interaction with multiple cellular processes such
that the normal capacity represents an extremely flexible and integrated signaling
module. In malignancy, however, these transcriptional choices and phenotypic out-
puts generally become restricted [35].
The diversity of VDR expression sites, being detected in virtually all cells of a
human, and the disparate phenotypic effects, from regulating calcium transport to
sensing redox potential and DNA damage, also suggests that the cell specificity of
actions may be distilled in a cell-type-specific manner. Therefore, the questions
emerge as to what governs the temporal regulation of VDR-dependent transcrit-
pomes, among different cell types. Recent findings suggest that a high level of
specificity of the timing and choice of VDR cofactor interactions may provide a
mechanistic basis for signaling specificity. Combined expression and choice of
interacting cofactors yield a high degree of NR transcriptional plasticity over
choice, and timing of gene regulation [32, 36, 37].
Of the principal corepressors, it remains to be established to what extent speci-
ficity and redundancy occur. The expression, localization, and isoforms of NCOR1
and NCOR2/SMRT corepressors strongly influence the spatio-temporal equilib-
rium between repressing and activating NR complexes and transcriptional outputs
[38]. The specificity of these corepressor interactions is beginning to emerge.
Ncor1 and Ncor2/Smrt knockouts are embryonically lethal, whereas stem cell com-
ponents from these mice and conditional approaches are revealing tissue-specific
interactions [39–41] with distinct interacting domains being used to distinguish NR
recognition [42]. Equally, the list continues to grow of novel corepressor proteins
that the VDR interacts with.
Compared to the relatively massive size of the corepressors NCOR1 and
NCOR2/SMRT, a number of smaller molecules have emerged as showing corepres-
sor function. TRIP15/COPS2/Alien has been demonstrated to interact with the
VDR and act as a corepressor, in an AF-2 independent manner that may not require
the same interactions with HDACs that NCOR1 does [43]. Intriguingly, this protein
contributes to the lid sub-complex of the 26S proteasome and thereby potentially
links VDR function with the regulation of protein stability [44]. Similarly, SLIRP
[45] has also emerged as a repressive factor for the VDR, although to date very little
is known about the specificity, in terms of tissue and target gene.