Transcription Enhancer Factor 3 (TEF3) Mediates the Expression of Down Syndrome Candidate Region 1 Isoform 1 (DSCR1-1L) in Endothelial Cells
Transcription Enhancer Factor 3 (TEF3) Mediates the Expression of Down Syndrome Candidate Region 1 Isoform 1 (DSCR1-1L) in Endothelial Cells
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DOI：
10.1074/jbc.m806338200
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发表时间：
2008-12-05
影响因子：
4.8
通讯作者：
Zeng, Huiyan
中科院分区：
文献类型：
--
作者：
Liu, Xin;Zhao, Dezheng;Zeng, Huiyan
唐氏综合征候选区1基因（DSCR 1）可以表达为四种亚型，其中之一是被充分研究的亚型4（DSCR 1 -4），其被VEGF-A（165）诱导以在VEGF-A（165）诱导的血管生成中提供负反馈环。我们以前报道过，在培养的内皮细胞和几种病理性血管生成的体内模型中，另一种DSCR 1亚型DSCR 1 - 1 L也被VEGF-A上调，并且与DSCR 1 -4不同，在Matrigel测定中，单独过表达DSCR 1 - 1 L诱导培养的内皮细胞增殖并促进血管生成。最近有报道，在DSCR 1基因敲除小鼠中，肿瘤生长被极大地抑制。虽然DSCR 1 -4的转录主要受NFAT的调控，但DSCR 1 - 1 L的调控机制尚不清楚。我们开发了人DSCR 1 - 1 L启动子驱动的荧光素酶系统，发现位于翻译起始位点上游1426 bp的推定保守的M-CAT位点的缺失使启动子活性钝化。我们进一步表明，TEF 3的敲低，而不是TEF家族的其他成员抑制VEGF-A（165）诱导的DSCR 1 - 1 L表达。我们还证明了TEF 3直接与DSCR 1 - 1 L启动子中假定的M-CAT位点在体外和体内相互作用。最后，即使在没有VEGF-A刺激的情况下，HUVEC中TEF 3同种型1而不是同种型3的过表达也足以诱导DSCR 1 - 1 L表达。综上所述，我们阐明了转录因子TEF 3的新功能。TEF 3通过与其启动子中的M-CAT位点结合而被DSCR 1 - 1 L表达所需，并且可能是抗血管生成治疗的有吸引力的靶点。
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-A(165) to provide a negative feedback loop in the VEGF-A(165)-induced angiogenesis. We reported previously that another DSCR1 isoform, DSCR1-1L, was also up-regulated by VEGF-A(165) 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-A(165)-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-A(165) 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.