Vascular endothelial growth factor receptor-2: counter-regulation by the transcription factors, TFII-I and TFII-IRD1.
The vascular endothelial growth factor receptor-2 (VEGFR-2/KDR/flk-1) functions as the primary mediator of vascular endothelial growth factor activation in endothelial cells. Regulation of VEGFR-2 expression appears critical in mitogenesis, differentiation, and angiogenesis. Transcriptional regulation of the VEGFR-2 is complex and may involve multiple putative upstream regulatory elements including E boxes. Transcript initiation is dependent on an initiator (Inr) element flanking the transcriptional start site. The transcription factor, TFII-I, enhances VEGFR-2 transcription in an Inr-dependent fashion. TFII-I is unusual both structurally and functionally. The TFII-I transcription factor family members contain multiple putative DNA binding domains. Functionally, TFII-I acts at both the basal, Inr element as well as at several distinct upstream regulatory sites. It has been postulated that the structure of TFII-I might allow simultaneous interaction with both basal and regulatory sites in a given promoter. As TFII-I is known to act at regulatory sites including E boxes as well as at the basal Inr element, we evaluated the possibility of Inr-independent TFII-I activation of the VEGFR-2 promoter. We found that an Inr-mutated VEGFR-2 reporter construct retains TFII-I-stimulated activity. We demonstrated that TFII-I binds to both the Inr and to three regulatory E boxes in the human VEGFR-2 promoter. In addition, reduction in TFII-I expression by siRNA results in decreased VEGFR-2 expression. We also describe counter-regulation of the VEGFR-2 promoter by TFII-IRD1. We found that TFII-I is capable of acting at both basal and regulatory sites in one promoter and that the human VEGFR-2 promoter is functionally counter-regulated by TFII-I and TFII-IRD1.
Jackson
Tanisha A
TA
Department of Medicine, The John Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Taylor
Harry E
HE
Sharma
Deva
D
Desiderio
Stephen
S
Danoff
Sonye K
SK
D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000494:pharmacology; D015534:Trans-Activators / Q000502:physiology*; D019473:Transcription Factors, TFII / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
C104259:GTF2I protein, human; C405493:GTF2IRD1 protein, human; D009124:Muscle Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D019473:Transcription Factors, TFII; D040301:Vascular Endothelial Growth Factor Receptor-2