Modulation of the Vitamin D3 Response by Cancer-Associated Mutant p53

Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11

“…R175H has previously been shown to reprogramme the cellular transcriptome through recruitment to novel target genes by various transcription factors such as NF-Y (Di Agostino et al, 2006), VDR (Stambolsky et al, 2010) and nuclear factor-kb (Schneider et al, 2010). Indeed, our pathway analysis also showed that the nuclear factor-kb-signalling pathway was strongly upregulated upon induced expression of p53-R175H (Supplementary Figure S5B), further confirming a role for nuclear factor-kb in the GOF of mutant p53 (Weisz et al, 2007).…”

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

“…Both mutations are within the DNAbinding domain of p53 and typical of skin tumors (Pfeifer and Besaratinia, 2009). Unlike p53 in normal KCs, of which levels are very low, mutant p53 is expressed at high levels, as in HaCaT cells, and retains the ability to functionally interact with the DNA (Stambolsky et al, 2010).…”

Mutant p53 is a transcriptional co-factor that binds to G-rich regulatory regions of active genes and generates transcriptional plasticity

“…Notably, a number of promoters that were reported to be regulated by bound mutp53 in other studies also overlap with CpG islands, e.g., MYC, 41 ID2, 42 ID4, 16 TWIST1, 9 EGR1, 22 MAP2K3, 43 target genes of the transcription factors VDR (CYP24A1) 14 and NF-Y (CCNA1, CCNB2, CDK1, CDC25C), 13 genes containing sterol regulatory elements in their promoters (CYP51A1, FDPS, FDFT1, HMGCR, HMGCS1, MVK, SQLE) 17 and the TDP2 gene. 18 G/C-rich DNA stretches are of particular interest regarding gene regulation.…”

“…Second, several effects of mutp53 on transcription of target genes of the transcription factors NF-Y, VDR and NF-kB, seem to require specific stimuli, like DNA damage, vitamin D or TNF-α treatment, respectively. 13,14,55 The fact that 83% of mutp53-bound promoters in U251 cells carry H3K4me3 indicates an active chromatin status of genes potentially regulated by mutp53. A detailed analysis of the mutp53-regulated genes GAS1 and HTR2A, as well as further genes containing reproducible mutp53 binding sites around their TSS, revealed alterations in active histone marks as well as RNA Pol II occupancy and processivity upon mutp53 depletion.…”

“…Via interactions with other TFs, mutp53 exerts either cooperative or counteracting effects on their target genes in a stimulusdependent or -independent manner. This scenario is illustrated, e.g., by the cooperation of mutp53 with NF-Y in positive regulation of CCAT-box containing cell cycle genes upon DNA damage, 13 the functional interaction of mutp53 with the vitamin D receptor (VDR) on its target genes after exposure of cells to vitamin D, 14 the SMAD-mediated antagonism between mutp53 and p63 activity in regulation of metastasis-related, TGF-β-induced genes, 15 the co-stimulation of the pro-angiogenic ID4 gene via mutp53-E2F1 protein complexes, 16 the binding of mutp53 to promoters of mevalonate pathway genes at least partly by interaction with SREBP transcription factors 17 and the promotion of etoposide resistance via ETS2-dependent co-regulation of the DNA repair related TDP2 gene. 18 A second scenario is based on the capacity of mutp53 to interact with structured DNA, like stem-loop structures 19 and non-B DNA structures formed by trinucleotide [(CAG)·(CTG)] n repeats.…”