title: The coordinated p53 and estrogen receptor cis-regulation at an FLT1 promoter SNP is specific to genotoxic stress and estrogenic compound.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Unit of Molecular Mutagenesis and DNA Repair, National Institute for Cancer Research, IST, Genoa, Italy.
authors.forename: Yari
authors.initials: Y
authors.lastname: Ciribilli
authors.forename: Virginia
authors.initials: V
authors.lastname: Andreotti
authors.forename: Daniel
authors.initials: D
authors.lastname: Menendez
authors.forename: Jan-Stephan
authors.initials: JS
authors.lastname: Langen
authors.forename: Gilbert
authors.initials: G
authors.lastname: Schoenfelder
authors.forename: Michael A
authors.initials: MA
authors.lastname: Resnick
authors.forename: Alberto
authors.initials: A
authors.lastname: Inga
mesh_terms: D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D004742:Enhancer Elements, Genetic; D004967:Estrogens / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics*; D020218:Response Elements / Q000235:genetics; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*
chemical_list: D004967:Estrogens; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D005472:Fluorouracil