The coordinated p53 and estrogen receptor cis-regulation at an FLT1 promoter SNP is specific to genotoxic stress and estrogenic compound.
| Autor: | Ciribilli Y; Unit of Molecular Mutagenesis and DNA Repair, National Institute for Cancer Research, IST, Genoa, Italy., Andreotti V, Menendez D, Langen JS, Schoenfelder G, Resnick MA, Inga A |
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| Jazyk: | angličtina |
| Zdroj: | PloS one [PLoS One] 2010 Apr 21; Vol. 5 (4), pp. e10236. Date of Electronic Publication: 2010 Apr 21. |
| DOI: | 10.1371/journal.pone.0010236 |
| Abstrakt: | 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 (1/2) 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 ERalpha 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. |
| Databáze: | MEDLINE |
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