Modulation of the vitamin D3 response by cancer-associated mutant p53.
The p53 gene is mutated in many human tumors. Cells of such tumors often contain abundant mutant p53 (mutp53) protein, which may contribute actively to tumor progression via a gain-of-function mechanism. We applied ChIP-on-chip analysis and identified the vitamin D receptor (VDR) response element as overrepresented in promoter sequences bound by mutp53. We report that mutp53 can interact functionally and physically with VDR. Mutp53 is recruited to VDR-regulated genes and modulates their expression, augmenting the transactivation of some genes and relieving the repression of others. Furthermore, mutp53 increases the nuclear accumulation of VDR. Importantly, mutp53 converts vitamin D into an antiapoptotic agent. Thus, p53 status can determine the biological impact of vitamin D on tumor cells.
Stambolsky
Perry
P
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel. perrystam@hotmail.com
Tabach
Yuval
Y
Fontemaggi
Giulia
G
Weisz
Lilach
L
Maor-Aloni
Revital
R
Siegfried
Zehava
Z
Sigfried
Zahava
Z
Shiff
Idit
I
Kogan
Ira
I
Shay
Moshe
M
Kalo
Eyal
E
Blandino
Giovanni
G
Simon
Itamar
I
Oren
Moshe
M
Rotter
Varda
V
D017209:Apoptosis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002762:Cholecalciferol / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D030181:Vitamin D Response Element / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D002762:Cholecalciferol