A single-nucleotide polymorphism in a half-binding site creates p53 and estrogen receptor control of vascular endothelial growth factor receptor 1.
Interactions between master regulatory pathways provide higher-order controls for cellular regulation. Recently, we reported a C-->T single-nucleotide polymorphism (SNP) in the vascular endothelial growth factor receptor 1 (VEGFR-1/Flt1) promoter that merges human VEGF and p53 pathways. This finding suggested a new layer in environmental controls of a pathway relevant to several diseases. The Flt1-T SNP created what appeared to be a half-site p53 target response element (RE). The absence of information about p53 gene responsiveness mediated by half-site REs led us to address how it influences Flt1 expression. We now identify a second regulatory sequence comprising a partial RE for estrogen receptors (ERs) upstream of the p53 binding site. Surprisingly, this provides for synergistic stimulation of transcription specifically at the Flt1-T allele through the combined action of ligand-bound ER and stress-induced p53. In addition to demonstrating direct control of Flt1 expression by ER and p53 proteins acting as sequence-specific transcription factors at half-site REs, we establish a new interaction between three master regulatory pathways, p53, ER, and VEGF. The mechanism of joint regulation through half-sites is likely relevant to transcriptional control of other targets and expands the number of genes that may be directly controlled in master regulatory networks.
Menendez
Daniel
D
Laboratory of Molecular Genetics MD3-01, National Institute of Environmental Health Sciences, 111 Alexander Drive, Research Triangle Park, NC 27709, USA.
Inga
Alberto
A
Snipe
Joyce
J
Krysiak
Oliver
O
Schönfelder
Gilbert
G
Resnick
Michael A
MA
D001665:Binding Sites; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000502:physiology*; D000077267:Fulvestrant; D006801:Humans; D008024:Ligands; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D020218:Response Elements; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D016159:Tumor Suppressor Protein p53; D000077267:Fulvestrant; D004958:Estradiol; D004317:Doxorubicin; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1