A single-nucleotide polymorphism in a half-binding site creates p53 and estrogen receptor control of vascular endothelial growth factor receptor 1.

Abstract:

: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.

journal_name

Mol Cell Biol

authors

Menendez D,Inga A,Snipe J,Krysiak O,Schönfelder G,Resnick MA

doi

10.1128/MCB.01742-06

subject

Has Abstract

pub_date

2007-04-01 00:00:00

pages

2590-600

issue

7

eissn

0270-7306

issn

1098-5549

pii

MCB.01742-06

journal_volume

27

pub_type

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