title: Differential roles for ETS, CREB, and EGR binding sites in mediating VEGF receptor 1 expression in vivo.
abstract: Vascular endothelial growth factor receptor 1 (VEGFR1) is a marker for endothelial-specific gene expression. We previously reported that the human VEGFR1 promoter (between -748 and +284) contains information for expression in the intact endothelium of transgenic mice. The objective of this study was to dissect the cis-regulatory elements underlying VEGFR1 promoter activity in vitro and in vivo. In primary endothelial cells, binding sites for E74-like factor 1 (ELF-1; between -49 and -52), cyclic adenosine monophosphate response element binding (CREB; between -74 and -81), and early growth response factor 1/3 (EGR-1/3; between -16 to -25) were shown to play a positive role in gene transcription, whereas a putative E26 transformation-specificsequence (ETS) motif between -36 and -39 had a net negative effect on promoter activity. When targeted to the Hprt locus of mice, mutations of the ELF-1 binding site and the CRE element reduced promoter activity in the embryonic vasculature and resulted in a virtual loss of expression in adult endothelium. Postnatally, the EGR binding site mutant displayed significantly reduced promoter activity in a subset of vascular beds. In contrast, mutation of the -39 ETS site resulted in increased LacZ staining in multiple vascular beds. Together, these results provide new insights into the transcriptional regulatory mechanisms of VEGFR1.
authors.affiliation: The Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Enjing
authors.initials: E
authors.lastname: Jin
authors.forename: Ju
authors.initials: J
authors.lastname: Liu
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Suehiro
authors.forename: Lei
authors.initials: L
authors.lastname: Yuan
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Okada
authors.forename: Vesna
authors.initials: V
authors.lastname: Nikolova-Krstevski
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Yano
authors.forename: Lauren
authors.initials: L
authors.lastname: Janes
authors.forename: David
authors.initials: D
authors.lastname: Beeler
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Spokes
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Regan
authors.forename: Shou-Ching
authors.initials: SC
authors.lastname: Shih
authors.forename: Peter
authors.initials: P
authors.lastname: Oettgen
authors.forename: Takashi
authors.initials: T
authors.lastname: Minami
authors.forename: William C
authors.initials: WC
authors.lastname: Aird
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics / Q000502:physiology; D050882:CREB-Binding Protein / Q000378:metabolism*; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D051776:Early Growth Response Protein 3 / Q000378:metabolism; D051765:Early Growth Response Transcription Factors / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*
chemical_list: C497325:EGR1 protein, human; C079945:EGR3 protein, human; C512897:ELF1 protein, human; D051766:Early Growth Response Protein 1; D051765:Early Growth Response Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D051776:Early Growth Response Protein 3; D050882:CREB-Binding Protein; D040281:Vascular Endothelial Growth Factor Receptor-1