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MDM2 binds and inhibits vitamin D receptor
#MMPMID25969952
Heyne K
; Heil TC
; Bette B
; Reichrath J
; Roemer K
Cell Cycle
2015[]; 14
(13
): 2003-10
PMID25969952
show ga
The E3 ubiquitin ligase and transcriptional repressor MDM2 is a potent inhibitor
of the p53 family of transcription factors and tumor suppressors. Herein, we
report that vitamin D receptor (VDR), another transcriptional regulator and
probably, tumor suppressor, is also bound and inhibited by MDM2. This interaction
was not affected by vitamin D ligand. VDR was ubiquitylated in the cell and its
steady-state level was controlled by the proteasome. Strikingly, overproduced
MDM2 reduced the level of VDR whereas knockdown of endogenous MDM2 increased the
level of VDR. In addition to ubiquitin-marking proteins for degradation, MDM2,
once recruited to promoters by DNA-binding interaction partners, can inhibit the
transactivation of genes. Transient transfections with a VDR-responsive
luciferase reporter revealed that low levels of MDM2 potently suppress
VDR-mediated transactivation. Conversely, knockdown of MDM2 resulted in a
significant increase of transcript from the CYP24A1 and p21 genes, noted cellular
targets of transactivation by liganded VDR. Our findings suggest that MDM2
negatively regulates VDR in some analogy to p53.
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