title: A SNP in the flt-1 promoter integrates the VEGF system into the p53 transcriptional network.
abstract: The VEGF system is essential for angiogenesis. VEGF overexpression frequently correlates with increased microvascularity and metastasis and decreased spontaneous apoptosis. Although a precise mechanism has not been established, studies suggest that VEGF expression is negatively regulated by p53, a master regulator and tumor suppressor. There are no reports of additional components of the VEGF signal transduction pathway being part of the p53 transcriptional network. A target of VEGF, the VEGF receptor 1/flt-1, can regulate growth and migration of endothelial cells and modulate angiogenesis. VEGF appears to be up-regulated in various cancers in which flt-1 may have a role in tumor progression and metastasis. We identified a C-to-T SNP upstream of the transcriptional start site in approximately 6% of the people examined. The SNP is located within a putative p53 response element. Only the promoter with the T SNP (FLT1-T) was responsive to p53 when examined with reporter assays or by endogenous gene expression analysis in cell lines with different SNP status. In response to doxorubicin-induced DNA damage, there was clear allele discrimination based on p53 binding at the FLT1-T but not FLT1-C promoters as well as p53-dependent induction of flt-1 mRNA, which required the presence of FLT1-T. Our results establish that p53 can differentially stimulate transcription at a polymorphic variant of the flt-1 promoter and directly places the VEGF system in the p53 stress-response network via flt-1 in a significant fraction of the human population. We suggest that the p53-VEGF-flt-1 interaction is relevant to risks in angiogenesis-associated diseases, including cancer.
authors.affiliation: Chromosome Stability Section, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, 111 Alexander Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Menendez
authors.forename: Oliver
authors.initials: O
authors.lastname: Krysiak
authors.forename: Alberto
authors.initials: A
authors.lastname: Inga
authors.forename: Bianca
authors.initials: B
authors.lastname: Krysiak
authors.forename: Michael A
authors.initials: MA
authors.lastname: Resnick
authors.forename: Gilbert
authors.initials: G
authors.lastname: Schönfelder
mesh_terms: D000483:Alleles; D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D018450:Disease Progression; D004317:Doxorubicin / Q000494:pharmacology; D005786:Gene Expression Regulation; D016158:Genes, p53; D006801:Humans; D008833:Microcirculation; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D004317:Doxorubicin; D004247:DNA; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1