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J. Biol. Chem., Vol. 283, Issue 49, 34159-34167, December 5, 2008

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Transcription Enhancer Factor 3 (TEF3) Mediates the Expression of Down Syndrome Candidate Region 1 Isoform 1 (DSCR1-1L) in Endothelial Cells^*

Xin Liu, Dezheng Zhao^¶, Liuliang Qin, Jian Li^||, and Huiyan Zeng¹

From the Department of Pathology, the ^¶Gastroenterology and ^||Cardiology Divisions, Department of Medicine, and the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston Massachusetts 02215

The Down syndrome candidate region 1 gene (DSCR1) can be expressed as four isoforms, one of which is the well-studied isoform 4 (DSCR1-4) that is induced by VEGF-A¹⁶⁵ to provide a negative feedback loop in the VEGF-A¹⁶⁵-induced angiogenesis. We reported previously that another DSCR1 isoform, DSCR1-1L, was also up-regulated by VEGF-A¹⁶⁵ in cultured endothelial cells and in several in vivo models of pathological angiogenesis and that different from DSCR1-4, DSCR1-1L overexpression alone induced cultured endothelial cell proliferation and promoted angiogenesis in Matrigel assays. It was reported recently that tumor growth was greatly repressed in DSCR1 knock-out mice. Although DSCR1-4 transcription was primarily regulated by NFAT, the mechanism regulating DSCR1-1L expression was still unknown. We developed human DSCR1-1L promoter-driven luciferase system and found that deletion of a putative conserved M-CAT site located 1426-bp upstream of the translation start site blunted promoter activity. We further showed that knockdown of TEF3, not other members of TEF family inhibited VEGF-A¹⁶⁵-induced DSCR1-1L expression. We also demonstrated that TEF3 directly interacted with the putative M-CAT site in the DSCR1-1L promoter in vitro and in vivo. Finally, overexpression of TEF3 isoform 1, not isoform 3, in HUVEC was sufficient to induce DSCR1-1L expression even in the absence of VEGF-A¹⁶⁵ stimulation. Taken together, we elucidated a novel function of transcriptional factor TEF3. TEF3 was required for DSCR1-1L expression through binding to the M-CAT site in its promoter and could be an attractive target for anti-angiogenesis therapy.

Received for publication, August 15, 2008 , and in revised form, October 6, 2008.

^* This work was supported by ACS Grant RSG-05-118-01-CSM. 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.

¹ To whom correspondence should be addressed: Dept. of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Ave. RN 270F, Boston, MA 02215. Tel.: 617-667-2329; Fax: 617-667-3591; E-mail: hzeng{at}caregroup.harvard.edu.

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