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J. Biol. Chem., Vol. 280, Issue 33, 29856-29863, August 19, 2005

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Vascular Endothelial Growth Factor Receptor-2

COUNTER-REGULATION BY THE TRANSCRIPTION FACTORS, TFII-I AND TFII-IRD1^*

Tanisha A. Jackson, Harry E. Taylor¶, Deva Sharma, Stephen Desiderio¶, and Sonye K. Danoff||

From the Department of Medicine and the ^¶Department of Molecular Biology and Genetics and Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

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.

Received for publication, January 10, 2005 , and in revised form, May 19, 2005.

^* This work was supported by American Lung Association Research Grant KO8-NS20193 and by a Beginning Grant-in-Aid from the American Heart Association Mid-Atlantic (to S. K. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Division of Pulmonary and Critical Care Medicine, Dept. of Medicine, The Johns Hopkins University School of Medicine, 1830 E. Monument St., 5th Fl., Baltimore, MD 21205. Tel.: 410-955-3467; Fax: 410-955-0036; E-mail: sdanoff{at}jhmi.edu.

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