The Coordinated P53 and Estrogen Receptor Cis-Regulation at an FLT1 Promoter SNP Is Specific to Genotoxic Stress and Estrogenic Compound

作者：Ciribilli Yari^*; Andreotti Virginia; Menendez Daniel; Langen Jan Stephan; Schoenfelder Gilbert; Resnick Michael A; Inga Alberto

来源：PLos One, 2010, 5(4): e10236.

DOI：10.1371/journal.pone.0010236

Background: Recently, we established that a C>T single nucleotide polymorphism (SNP) in the promoter of the VEGF receptor FLT1 gene generates a 1/2 site p53 response element (RE-T) that results in p53 responsiveness of the promoter. The transcriptional control required an estrogen receptor (ER) 1/2 site response element (ERE1) 225 nt upstream to the RE-T.
Methodology/Principal Findings: Here we report the identification of a second ER K site (ERE2) located 145 bp downstream of the RE-T and establish that both EREs can impact p53-mediated transactivation of FLT1-T in a manner that is cell type and ER level dependent. Gene reporter assays and ChIP experiments conducted in the breast cancer-derived MCF7 cells revealed that the ERE2 site was sufficient for p53-mediated ER alpha recruitment and transactivation of the FLT1-T promoter/reporter construct. Surprisingly, unlike the case for other p53 target promoters, p53-mediated transactivation of FLT1-T constructs or expression of the endogenous FLT1 gene, as well as binding of p53 and ER at the promoter constructs, was inducible by doxorubicin but not by 5-fluorouracil. Furthermore, ER activity at FLT1-T was differentially affected by ER ligands, compared to a control TFF1/pS2 ER target promoter. The p53-related transcription factors (TFs) p73 and p63 had no effect on FLT1 transactivation.
Conclusions/Significance: We establish a new dimension to the p53 master regulatory network where p53-mediated transcription from a 1/2 site RE can be determined by ER binding at one or more cis-acting EREs in manner that is dependent on level of ER protein, the type of ER ligand and the specific p53-inducing agent.

• 出版日期2010-4-21