Page 211 - Vitamin D and Cancer

198 F.S.G. Cheung and J.K.V. Reichardt

The AF-2 domain of the VDR becomes exposed upon 1,25(OH) D binding and
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serves as a binding platform for transcriptional activators [110]. Kim et al. investigated
the recruitment of co-factors in 1,25(OH) D induced gene expression. These co-factors
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possessing HAT activity and include members of the p160 co-activators (steroid recep-
tor co-activators (SRC)-1, SRC-2 and SRC-3), CREB binding protein (CBP)/p300 co-
activators [83] and nuclear co-activator 62 kDa-SKI-interacting protein (NCoA62-SKIP)
[7]. After the chromatin is relaxed by acetylation, the vitamin D receptor interacting
proteins (DRIPs) complex at the AF-2 region facilitates the entry of transcription
machinery proteins, such as RNA polymerase (Pol) II [52] and transcription factor 2B
(TF2B) [94]. Different nuclear hormone receptors may direct tissue specific gene regu-
lation by recruiting various members of the HAT proteins/co-activators [148].
On the other hand, 1,25(OH) D can also repress gene expression. The repres-
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sion is mediated by the binding of 1,25(OH) D to VDR to induce the interaction
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of the VDR to VDR-interacting repressor (VDIR) which can bind to a negative
VDRE (nVDRE). Binding of VDIR to this motif leads to the replacement of HAT
with HDAC [108]. It has recently been found that this VDIR-VDR co-repressor
complex together with HDAC recruits the DNA methyltransferase which methy-
lates CpG sites [82]. At this stage MeCP2 can bind to the methylated CpG
sequences and repress transcription by interacting with the HDAC complex [95].
Therefore, the HDAC and methylation activities work in parallel to mediate
1,25(OH) D induced trans-repression of VDR target genes.
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9.3.3 Non-genomic Actions of 1,25-Dihydroxyvitamin D
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In 1,25(OH) D , the single bond between the A ring and the fused C-D rings allows
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rotation of the A ring around the C-D fused rings. This flexibility creates the forma-
tion of trans and cis conformations of the molecule that dictates the type of
response elicited by the molecule [113, 114]. Apart from the genomic effect
described earlier, in the mid-1980s, a rapid, nongenomic response was recognized
and is mediated by the cis-1,25(OH) D [112]. This molecule has the ability to
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activate multiple cell-signalling cascades and bring about a broad range of effects
in cell survival and proliferation [115].
Non-genomic actions of 1,25(OH) D involves the binding of 1,25(OH) D to a
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cell surface membrane receptor. It has been well documented that non genomic
pathway involves the activation of the Raf-mitogen-activated protein kinase extra-
cellular signal-regulated kinase kinase (MEK)-mitogen-activated protein kinase
(MAPK)-extracellular signal-regulated kinase (ERK) cascade. However, the recep-
tor and the exact pathways that lead to the activation of Raf are still to be confirmed.
Candidates for this putative surface membrane receptor include the classical cyto-
solic VDR (called VDR ) [75, 84] and the 1,25(OH) D -membrane associated
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rapid response steroid-binding (1,25(OH) D –MARRS) protein [111].
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It has been proposed that the binding of 1,25(OH) D to G protein coupled recep-
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tors or protein-tyrosine kinase receptors [100] is an essential part of the non-genomic