Requirement of the nuclear localization of transcription enhancer factor 3 for proliferation, migration, tube formation, and angiogenesis induced by vascular endothelial growth factor

Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
The FASEB Journal (Impact Factor: 5.04). 12/2010; 25(4):1188-97. DOI: 10.1096/fj.10-167619
Source: PubMed


Transcription enhancer factor 3 (TEF3) is known to regulate the expression of muscle-specific genes and to play important roles in muscle development and diseases. However, little is known about its role in vascular endothelial growth factor (VEGF)-induced angiogenesis. Most recently, we discovered a novel function of TEF3, in which TEF3 is required for the up-regulation of a proangiogenic factor, Down syndrome candidate region 1 isoform 1L (DSCR1-1L), induced by VEGF-A(165) in endothelial cells. Overexpression of TEF3 isoform 1 (TEF3-1) is sufficient to induce DSCR1-1L expression. Here, we report that knocking down the expression of TEF3 almost completely inhibits VEGF-A(165)-induced proliferation, migration, tube formation, formation of F-actin stress fiber, and in vivo Matrigel angiogenesis. This inhibition cannot be rescued by DSCR1-1L overexpression. Further, overexpression of TEF3-1, but not its nuclear localization signal-deletion mutant (TEF3-ΔNLS), induces human umbilical vein endothelial cell proliferation, migration, tube formation, and formation of F-actin stress fiber, even in the absence of VEGF-A(165) stimulation, which is partially inhibited by DSCR1-1L silencing. Our data demonstrate that TEF3, mainly its nuclear localization, is required for VEGF-A(165)-induced endothelial proliferation, migration, tube formation, and in vivo Matrigel angiogenesis.

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    • "ed in cultured vascular endothelial cells by VEGF - A 165 and provides a negative feedback loop that inhibits VEGF - A 165 - induced angiogenesis ( Hesser et al . 2004 ; Liu et al . 2003 ; Minami et al . 2004 ) . Furthermore , RTEF - 1 was shown to be required for VEGF - induced HUVEC proliferation , migration , tube formation , and angiogenesis ( Liu et al . 2011 ) ."
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    ABSTRACT: The transcriptional enhancer factor (TEF) multigene family is primarily functional in muscle-specific genes through binding to MCAT elements that activate or repress transcription of many genes in response to physiological and pathological stimuli. Among the TEF family, TEF-1, RTEF-1, and DTEF-1 are critical regulators of cardiac and smooth muscle-specific genes during cardiovascular development and cardiac disorders including cardiac hypertrophy. Emerging evidence suggests that in addition to functioning as muscle-specific transcription factors, members of the TEF family may be key mediators of gene expression induced by hypoxia in endothelial cells by virtue of its multidomain organization, potential for post-translational modifications, and interactions with numerous transcription factors, which represent a cell-selective control mediator of nuclear signaling. We review the recent literature demonstrating the involvement of the TEF family of transcription factors in the regulation of differential gene expression in cardiovascular physiology and pathology.
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    ABSTRACT: In the preimplantation mouse embryo, TEAD4 is critical to establishing the trophectoderm (TE)-specific transcriptional program and segregating TE from the inner cell mass (ICM). However, TEAD4 is expressed in the TE and the ICM. Thus, differential function of TEAD4 rather than expression itself regulates specification of the first two cell lineages. We used ChIP sequencing to define genomewide TEAD4 target genes and asked how transcription of TEAD4 target genes is specifically maintained in the TE. Our analyses revealed an evolutionarily conserved mechanism, in which lack of nuclear localization of TEAD4 impairs the TE-specific transcriptional program in inner blastomeres, thereby allowing their maturation toward the ICM lineage. Restoration of TEAD4 nuclear localization maintains the TE-specific transcriptional program in the inner blastomeres and prevents segregation of the TE and ICM lineages and blastocyst formation. We propose that altered subcellular localization of TEAD4 in blastomeres dictates first mammalian cell fate specification.
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