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Molecular and Cellular Biology, April 2007, p. 2590-2600, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01742-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Single-Nucleotide Polymorphism in a Half-Binding Site Creates p53 and Estrogen Receptor Control of Vascular Endothelial Growth Factor Receptor 1{triangledown} ,{dagger}

Daniel Menendez,1,{ddagger} Alberto Inga,2,{ddagger} Joyce Snipe,1 Oliver Krysiak,3 Gilbert Schönfelder,3 and Michael A. Resnick1*

Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina,1 Molecular Mutagenesis Unit, National Institute for Cancer Research, IST, Genoa, Italy,2 Institute of Clinical Pharmacology-Toxicology, Charité-Universitaetsmedizin, Berlin, Germany3

Received 15 September 2006/ Returned for modification 15 November 2006/ Accepted 10 January 2007

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.

* Corresponding author. Mailing address: National Institute of Environmental Health Sciences, Laboratory of Molecular Genetics, MD3-01, 111 Alexander Dr., Research Triangle Park, NC 27709. Phone: (919) 541-4480. Fax: (919) 541-7593. E-mail: resnick{at}niehs.nih.gov.

{triangledown} Published ahead of print on 22 January 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} D.M. and A.I. contributed equally to this work.

Molecular and Cellular Biology, April 2007, p. 2590-2600, Vol. 27, No. 7
0270-7306/07/$08.00+0     doi:10.1128/MCB.01742-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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