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• W2080371298 abstract "Coordinated gene regulation within the vascular endothelium is required for normal cardiovascular patterning during development and for vascular homeostasis during adulthood, yet little is known about the mechanisms that regulate endothelial transcriptional events. Vascular endothelial zinc finger 1 (Vezf1)/DB1 is a recently identified zinc finger-containing protein that is expressed specifically within endothelial cells during development. In this report, we demonstrate that Vezf1/DB1 is a nuclear localizing protein that potently and specifically activates transcription mediated by the human endothelin-1 promoter, in a Tax-independent manner, in transient transfection assays. Using a combination of deletion mutagenesis and electrophoretic mobility shift assays, a novel Vezf1/DB1-responsive element was localized to a 6-base pair (bp) motif, ACCCCC, located 47 bp upstream of the endothelin-1 transcription start site. Recombinant Vezf1/DB1 also bound to this sequence, and a 2-bp mutation in this element abolished Vezf1/DB1 responsiveness by the endothelin-1 promoter. Vezf1/DB1 could be identified with a specific antibody in nuclear complexes from endothelial cells that bound to this element. Regulation of endothelin-1 promoter activity by Vezf1/DB1 provides a mechanism for endothelin-1 expression in the vascular endothelium during development and to maintain vascular tone; Vezf1/DB1 itself is a candidate transcription factor for modifying endothelial cell phenotypes in order to appropriately assemble and maintain the cardiovascular system. Coordinated gene regulation within the vascular endothelium is required for normal cardiovascular patterning during development and for vascular homeostasis during adulthood, yet little is known about the mechanisms that regulate endothelial transcriptional events. Vascular endothelial zinc finger 1 (Vezf1)/DB1 is a recently identified zinc finger-containing protein that is expressed specifically within endothelial cells during development. In this report, we demonstrate that Vezf1/DB1 is a nuclear localizing protein that potently and specifically activates transcription mediated by the human endothelin-1 promoter, in a Tax-independent manner, in transient transfection assays. Using a combination of deletion mutagenesis and electrophoretic mobility shift assays, a novel Vezf1/DB1-responsive element was localized to a 6-base pair (bp) motif, ACCCCC, located 47 bp upstream of the endothelin-1 transcription start site. Recombinant Vezf1/DB1 also bound to this sequence, and a 2-bp mutation in this element abolished Vezf1/DB1 responsiveness by the endothelin-1 promoter. Vezf1/DB1 could be identified with a specific antibody in nuclear complexes from endothelial cells that bound to this element. Regulation of endothelin-1 promoter activity by Vezf1/DB1 provides a mechanism for endothelin-1 expression in the vascular endothelium during development and to maintain vascular tone; Vezf1/DB1 itself is a candidate transcription factor for modifying endothelial cell phenotypes in order to appropriately assemble and maintain the cardiovascular system. endothelin-1 vascular endothelial zinc finger 1 activator protein 1 hypoxia inducible factor 1 human endothelin-1 myocardial endothelial cells glutathione S-transferase green fluorescent protein carboxyl terminus of Hsc70-interacting protein cytomegalovirus base pair(s) electrophoretic mobility shift assay The endothelium maintains vascular integrity during adulthood by regulating vascular tone, lymphocyte trafficking, vessel growth, and hemostasis (1Griendling K.K. Alexander R.W. FASEB J. 1996; 10: 283-292Crossref PubMed Scopus (134) Google Scholar). In particular, the vascular endothelium modulates vascular tone and blood pressure through the coordinated production of potent vasoactive molecules. In addition, the endothelium directs formation of the vascular system during development through its role in the processes of vasculogenesis (development of blood vessels from angioblasts in situ) andangiogenesis (sprouting of new vessels from existing vessels) (2Risau W. Flamme I. Annu. Rev. Cell Dev. Biol. 1995; 11: 73-91Crossref PubMed Scopus (1337) Google Scholar). Whereas endothelial mechanisms during development and in adulthood may seem discrete, there is now strong evidence that they overlap considerably, and that molecules required for normal vascular development may contribute to vascular homeostasis in adulthood, and vice versa.Endothelin-1 (ET-1),1 a 21-amino acid peptide originally isolated from porcine endothelial cells (3Yanagisawa M. Kurihara H. Kimura S. Tomobe Y. Kobayashi M. Mitsui Y. Yazaki Y. Goto K. Masaki T. Nature. 1988; 332: 411-415Crossref PubMed Scopus (10185) Google Scholar), provides one example of an endothelial cell protein that is critical both for cardiovascular development in the embryo and for vascular homeostasis in the adult. ET-1, which is expressed primarily in endothelial cells and also epithelial cells of the branchial arches during development (4Thomas T. Kurihara H. Yamagishi H. Kurihara Y. Yazaki Y. Olson E.N. Srivastava D. Development. 1998; 125: 3005-3014PubMed Google Scholar), is required for the development of neural crest-derived tissues arising from the branchial arches, such as the great vessels, the ventricular septum, and craniofacial structures (5Kurihara Y. Kurihara H. Oda H. Maemura K. Nagai R. Ishikawa T. Yazaki Y. J. Clin. Invest. 1995; 96: 293-300Crossref PubMed Scopus (331) Google Scholar). These effects seem to be mediated via interactions with the endothelin-A receptor, which is expressed in neural crest cells. Loss of ET-1 signaling leads to apoptosis of post-migratory neural crest-derived mesenchymal cells, with resultant cardiovascular defects such as ventricular septal defects, truncus arteriosus, and interruption of the aortic arch.In addition to its function as a critical developmental signal for the cardiovascular system, ET-1 has potent and complex effects on the adult vasculature. ET-1 has direct vasoconstrictor effects on vascular smooth muscle cells, and sensitizes smooth muscle cells to the effects of angiotensin II and norepinephrine (6Miller W.L. Redfield M.M. Burnett J.C. J. Clin. Invest. 1989; 83: 317-320Crossref PubMed Scopus (497) Google Scholar). ET-1 also stimulates the release of aldosterone and nitric oxide, the latter effect indicating that the vasoconstrictor effects of ET-1 may be most pronounced when endothelial function is compromised. The effects of ET-1 are linked pathophysiologically to the development of hypertension, cardiac hypertrophy (7Ito H. Hirata Y. Hiroe M. Tsujino M. Adachi S. Takamoto T. Nitta M. Taniguchi K. Marumo F. Circ. Res. 1991; 69: 209-215Crossref PubMed Scopus (460) Google Scholar), and ischemic heart disease (8Serneri G.G. Cecioni I. Vanni S. Paniccia R. Bandinelli B. Vetere A. Janming X. Bertolozzi I. Boddi M. Lisi G.F. Sani G. Modesti P.A. Circ. Res. 2000; 86: 377-385Crossref PubMed Google Scholar).Given the bifunctional role of ET-1 in development and in vascular homeostasis, it is not surprising that its expression and activity are tightly regulated at the transcriptional level. The humanET-1 gene has a TATA box-containing promoter, and severalcis-acting elements have been implicated in transcriptional regulation of ET-1 mRNA. An upstream activator protein-1 (AP-1) site located at position −117, which is bound by c-fos and c-jun, is required for inducible high-level ET-1 promoter activity (9Lee M.E. Dhadly M.S. Temizer D.H. Clifford J.A. Yoshizumi M. Quertermous T. J. Biol. Chem. 1991; 266: 19034-19039Abstract Full Text PDF PubMed Google Scholar). In addition, a GATA motif at position −135, which is bound by the zinc finger transcription factor GATA-2 in endothelial cells (10Lee M.E. Temizer D.H. Clifford J.A. Quertermous T. J. Biol. Chem. 1991; 266: 16188-16192Abstract Full Text PDF PubMed Google Scholar), is crucial to the basal and regulated expression of the ET-1 gene. Furthermore, the cooperativity between the AP-1 complex and GATA-2 leads to a synergistic increase in trans-activation ofET-1 (11Kawana M. Lee M. Quertermous E. Quertermous T. Mol. Cell. Biol. 1995; 15: 42256-44231Crossref Scopus (178) Google Scholar). Last, hypoxia-mediated expression of ET-1 is mediated via trans-activation of the ET-1promoter by hypoxia-inducible factor-1 (HIF-1) (12Yamashita K. Discher D.J. Hu J. Bishopric N.H. Webster K.A. J. Biol. Chem. 2001; 276: 12645-12653Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar). However, the expression of fos/jun and GATA-2 is not restricted to endothelial cells, and the up-regulation of theET-1 gene via the GATA motif is not limited to GATA-2, as other members of the GATA family, such as GATA-1 and GATA-3, exert a similar effect (11Kawana M. Lee M. Quertermous E. Quertermous T. Mol. Cell. Biol. 1995; 15: 42256-44231Crossref Scopus (178) Google Scholar). Because GATA-2, HIF-1, and the Fos and Jun family members are expressed more promiscuously than is ET-1, the action of these factors alone cannot be responsible for the cell type-restricted activation of the ET-1 gene. Therefore, it is possible that the binding of the trans-acting factors to these sites may recruit or otherwise cooperate with additional proteins which are important for cell restricted expression of theET-1 gene. In any event, a 6-kilobase fragment of the mouse ET-1 promoter confers vascular-specific expression in transgenic mice (13Harats D. Kurihara H. Belloni P. Oakley H. Ziober A. Ackley D. Cain G. Kurihara Y. Lawn R. Sigal E. J. Clin. Invest. 1995; 95: 1335-1344Crossref PubMed Scopus (120) Google Scholar).Vezf1/DB1 is a recently identified endothelial cell-specific protein. A retroviral trap screen identified a 56-kDa protein expressed specifically in the vascular endothelium, vascular endothelial zinc finger 1 (Vezf1) (14Xiong J.W. Leahy A. Lee H.H. Stuhlmann H. Dev. Biol. 1999; 206: 123-141Crossref PubMed Scopus (61) Google Scholar). Vezf1, which is the mouse homologue of a previously identified but incompletely characterized human protein called DB1 (15Koyano-Nakagawa N. Nishida J. Baldwin D. Arai K. Yokota T. Mol. Cell. Biol. 1994; 14: 5099-5107Crossref PubMed Scopus (42) Google Scholar), is a putative transcription factor that contains 6 Cys2/His2-type zinc finger motifs, as well as a glutamine-stretch and a proline-rich region characteristic of transcriptional activation or repression domains. Vezf1/DB1 is first expressed in the anterior-most mesoderm at day 7.25 post-conception. Expression remains restricted to the vascular endothelium through at least day 13.5 and is detectable in endothelial cells undergoing both angiogenesis and vasculogenesis (14Xiong J.W. Leahy A. Lee H.H. Stuhlmann H. Dev. Biol. 1999; 206: 123-141Crossref PubMed Scopus (61) Google Scholar). Vezf1/DB1 is therefore an attractive candidate as a potential transcription factor for mediating endothelial cell-specific gene expression, and is expressed in the correct spatial and temporal sequence during embryogenesis to regulate genes critical for endothelial cell differentiation, cardiovascular development, and/or angiogenesis. In an effort to identify transcriptional targets for Vezf1/DB1 in vascular endothelial cells, we have found that Vezf1/DB1 potently trans-activates the human endothelin-1 (hET-1) promoter, and we have characterized a novel Vezf1/DB1-responsive element in the ET-1 5′-flanking sequence.DISCUSSIONIn this report, we identify Vezf1/DB1 as an endothelial cell-specific transcription factor. We also characterize a logical transcriptional target, and the DNA response element through which this target is chosen. Vezf1/DB1 potently trans-activates the hET-1 5′-flanking sequence through a novel response element, ACCCCC, to mediate high level transcriptional activity of this promoter. Proteins from endothelial cell nuclear extracts bind specifically to this essential response element, and endogenous Vezf1/DB1 exists as a component of this binding activity. These results provide convincing evidence that Vezf1/DB1 acts as a transcription factor and thatET-1 is a transcriptional target for this protein. In addition, these studies provide a rational explanation for inducible expression of ET-1 specifically within the vascular endothelium.Vezf1/DB1 was first identified by screening an expression library with a GC-rich Tax-responsive element within the interleukin-3 promoter (15Koyano-Nakagawa N. Nishida J. Baldwin D. Arai K. Yokota T. Mol. Cell. Biol. 1994; 14: 5099-5107Crossref PubMed Scopus (42) Google Scholar). Recombinant Vezf1/DB1 could bind to this GC-rich sequence by EMSA; however, Vezf1/DB1 by itself was not able totrans-activate the interleukin-3 promoter, although it did modulate Tax-mediated trans-activation in a phorbol ester-dependent fashion. We have similarly seen low-affinity interactions between Vezf1/DB1 and GC-rich regions within the KDR/flk-1 promoter in EMSA experiments, 2J. Aitsebaomo and C. Patterson, unpublished observations. yet Vezf1/DB1 does not trans-activate the KDR/flk-1 promoter (Fig.2A). Therefore, we suspect these low affinity interactions with GC-rich sequences may not be physiologically significant. In contrast, the highly specific interactions identified between Vezf1/DB1 and the ACCCCC motif result in potent trans-activation of the ET-1 promoter. These observations, in conjunction with the overlapping expression pattern of Vezf1/DB1 and ET-1 during development (4Thomas T. Kurihara H. Yamagishi H. Kurihara Y. Yazaki Y. Olson E.N. Srivastava D. Development. 1998; 125: 3005-3014PubMed Google Scholar, 14Xiong J.W. Leahy A. Lee H.H. Stuhlmann H. Dev. Biol. 1999; 206: 123-141Crossref PubMed Scopus (61) Google Scholar), makes regulation of ET-1 by Vezf1/DB1 a more plausible physiologic interaction to regulate gene expression in vascular endothelial cells. The ACCCCC sequence characterized in these studies as the Vezf1/DB1-binding site and response element does not exactly correspond to any previously identified transcription factor-binding sites, as determined by searches of the TRANSFAC data base. However, it is interesting to note that MAZ, which is closely related to Vezf1/DB1 and also contains 6 highly similar zinc fingers of the Cys2/His2 type, binds to response elements containing stretches of G or C residues (23Her S. Bell R.A. Bloom A.K. Siddall B.J. Wong D.L. J. Biol. Chem. 1999; 274: 8698-8707Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 24Parks C.L. Shenk T. J. Biol. Chem. 1996; 271: 4417-4430Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar), suggesting that this family of transcription factors may have particularly high affinity for homopolymeric stretches of G/C residues. Identification of a defined Vezf1/DB1-binding site will aid in the discovery of other Vezf1/DB1-responsive genes within the vascular endothelium.The studies presented here do not specifically address how Vezf1/DB1 activity itself is regulated, and what the consequences of differences in Vezf1/DB1 activity might mean with respect to ET-1 expression, although some interesting hypotheses can be generated based on our observations and those of others. ET-1 expression in endothelial cells is known to be dependent on Rho GTPase activity, and Rho signaling itself can directly activate the ET-1 promoter (25Hernandez-Perera O. Perez-Sala D. Soria E. Lamas S. Circ. Res. 2000; 87: 616-622Crossref PubMed Scopus (173) Google Scholar). This effect may have particular importance with respect to modulating vasoconstrictive, migratory, and proliferative effects of cells that are ET-1-responsive, such as smooth muscle and neural crest cells, especially since Rho signaling pathways down-regulate endothelial nitric-oxide synthase (26Laufs U. Liao J.K. J. Biol. Chem. 1998; 273: 24266-24271Abstract Full Text Full Text PDF PubMed Scopus (966) Google Scholar), which opposes the actions of ET-1 within the vasculature. The relationship between ET-1 expression and Rho signaling is significant because physical interactions have been demonstrated between Vezf1/DB1 and the fraction of prenylated RhoB that is localized to the nucleus (27Lebowitz P.F. Prendergast G.C. Cell. Adhes. Commun. 1998; 6: 277-287Crossref PubMed Scopus (33) Google Scholar). It is tempting to speculate that Vezf1/DB1 serves, at least in part, to mediate Rho-dependent signaling events, such as ET-1 expression, at the transcriptional level in endothelial cells.Although previous data provide few insights into the function of Vezf1/DB1, the expression of this gene during development argues strongly for a specific role in vascular development. The expression of Vezf1/DB1 overlaps significantly during development with KDR/flk-1 (14Xiong J.W. Leahy A. Lee H.H. Stuhlmann H. Dev. Biol. 1999; 206: 123-141Crossref PubMed Scopus (61) Google Scholar), a receptor for vascular endothelial growth factor and a marker for endothelial cells and their precursors during development in the mouse (28Shalaby F. Rossant J. Yamaguchi T.P. Gertsenstein M. Wu X.-F. Breitman M. Schuh A. Nature. 1995; 376: 62-66Crossref PubMed Scopus (3332) Google Scholar). This would suggest: 1) that Vezf1/DB1 may lie upstream of KDR/flk-1 by up-regulating its expression; 2) that Vezf1/DB1 is induced in KDR/flk-1-expressing cells; or 3) that KDR/flk-1 and Vezf1/DB1 are regulated in parallel, possibly through similar mechanisms. We have found no evidence for the first possibility, that Vezf1/DB1 regulates expression of KDR/flk-12 (Fig. 2A). Instead, we find that Vezf1/DB1 trans-activates ET-1, which appears later than KDR/flk-1 during vascular development. Deficiency of ET-1 during development results in branchial arch abnormalities, leading to defects in branchial arch artery development and subsequent malformation of the great vessels and cardiac outflow tract abnormalities, as well as characteristic craniofacial abnormalities (4Thomas T. Kurihara H. Yamagishi H. Kurihara Y. Yazaki Y. Olson E.N. Srivastava D. Development. 1998; 125: 3005-3014PubMed Google Scholar,5Kurihara Y. Kurihara H. Oda H. Maemura K. Nagai R. Ishikawa T. Yazaki Y. J. Clin. Invest. 1995; 96: 293-300Crossref PubMed Scopus (331) Google Scholar). If the effects of Vezf1/DB1 on ET-1 expression observed in the present studies are representative of regulatory events that are critical in endothelial cells during vascular development, then absence of Vezf1/DB1 in mice should phenocopy, at least partially,ET-1-null mice. Experiments to delete Vezf1/DB1 in mice by homologous recombination will determine whether the molecular events described in the present studies are essential for the regulation ofET-1 during development.Although cell type-specific gene regulation is beginning to be understood for many lineages, such as skeletal myocytes (29Olson E.N. Klein W.H. Genes Dev. 1994; 8: 1-8Crossref PubMed Scopus (606) Google Scholar) and smooth muscle cells (30Owens G.K. Acta Physiol. Scand. 1998; 164: 623-635Crossref PubMed Scopus (113) Google Scholar), there is still little known about the transcriptional mechanisms that regulate cell type-specific gene expression in the vascular endothelium. For example, KDR/flk-1 is a well characterized marker for vascular endothelial cells during development, and studies have demonstrated the importance of a variety of transcription factors in control of its expression, including Sp1 (31Patterson C. Wu Y. Lee M.-E. DeVault J.D. Runge M.S. Haber E. J. Biol. Chem. 1997; 272: 8410-8416Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar), TFII-I (21Wu Y. Patterson C. J. Biol. Chem. 1999; 274: 3207-3214Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar), and GATA proteins (32Kappel A. Schlaeger T.M. Flamme I. Orkin S.H. Risau W. Breier G. Blood. 2000; 96: 3078-3085Crossref PubMed Google Scholar, 33Minami T. Rosenberg R.D. Aird W.C. J. Biol. Chem. 2001; 276: 5395-5402Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). However, none of these proteins by themselves account for the restricted pattern of KDR/flk-1 expression during development. Similarly, GATA-2, AP-1, and HIF-1 have all been implicated in the transcriptional regulation of ET-1 (9Lee M.E. Dhadly M.S. Temizer D.H. Clifford J.A. Yoshizumi M. Quertermous T. J. Biol. Chem. 1991; 266: 19034-19039Abstract Full Text PDF PubMed Google Scholar, 10Lee M.E. Temizer D.H. Clifford J.A. Quertermous T. J. Biol. Chem. 1991; 266: 16188-16192Abstract Full Text PDF PubMed Google Scholar,12Yamashita K. Discher D.J. Hu J. Bishopric N.H. Webster K.A. J. Biol. Chem. 2001; 276: 12645-12653Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar), yet the means by which ET-1 expression is induced specifically within the vascular endothelium is still not explained.Several reports have implicated Ets family members in endothelial development and cell type-specific gene regulation (34Brown L.A. Rodaway A.R. Schilling T.F. Jowett T. Ingham P.W. Patient R.K. Sharrocks A.D. Mech. Dev. 2000; 90: 237-252Crossref PubMed Scopus (227) Google Scholar, 35Dube A. Akbarali Y. Sato T.N. Libermann T.A. Oettgen P. Circ. Res. 1999; 84: 1177-1185Crossref PubMed Scopus (92) Google Scholar); however, most of these proteins are expressed in many lineages other than endothelial cells, so Ets proteins are likely required to cooperate with factors that are expressed in a more restricted fashion to mediate endothelial cell gene regulation. The helix-loop-helix transcription factor SCL/tal-1 has been implicated in endothelium-specific transcriptional events as well. Although SCL/tal-1 is dispensable for endothelial cell specification but required for generation of all hematopoietic lineages (36Robb L. Lyons I. Li R. Hartley L. Kontgen F. Harvey R.P. Metcalf D. Begley C.G. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7075-7079Crossref PubMed Scopus (479) Google Scholar, 37Shivdasani R.A. Mayer E.L. Orkin S.H. Nature. 1995; 373: 432-434Crossref PubMed Scopus (775) Google Scholar, 38Robb L. Elwood N.J. Elefanty A.G. Kontgen F. Li R. Barnett L.D. Begley C.G. EMBO J. 1996; 15: 4123-4129Crossref PubMed Scopus (284) Google Scholar), a role in endothelial pattern formation has been attributed to SCL/tal-1 (39Visvader J.E. Fujiwara Y. Orkin S.H. Genes Dev. 1998; 12: 473-479Crossref PubMed Scopus (278) Google Scholar). These data would suggest that SCL/tal-1 functions to direct endothelial cell gene expression in early stages of development, although this conclusion has been drawn into question by the demonstration that these effects of SCL/tal-1 are DNA-binding independent (40Porcher C. Liao E.C. Fujiwara Y. Zon L.I. Orkin S.H. Development. 1999; 126: 4603-4615Crossref PubMed Google Scholar). In any event, endothelial transcriptional targets for SCL/tal-1 have not been well characterized, and the prominent role of SCL/tal-1 in hematopoietic transcriptional events indicates that SCL/tal-1 cannot, by itself, explain endothelial cell type-specific gene expression. In contrast, the identification of Vezf1/DB1 as a developmentally regulated, endothelial specific protein (14Xiong J.W. Leahy A. Lee H.H. Stuhlmann H. Dev. Biol. 1999; 206: 123-141Crossref PubMed Scopus (61) Google Scholar), and our demonstration here that it is a nuclear localizing protein that functions as a transcriptional activator, indicates that Vezf1/DB1 may serve as an important missing link in our understanding of endothelial cell type-specific gene regulation. Although further studies will be necessary to determine the range of endothelial cell genes that are regulated by Vezf1/DB1, and the functional role of this protein in the modulation of endothelial cell phenotypes, our studies support the hypothesis that Vezf1/DB1, in cooperation with other transcription factors yet to be determined, assists in the cellular process of determining the complement of genes that are expressed within the vascular endothelium. The endothelium maintains vascular integrity during adulthood by regulating vascular tone, lymphocyte trafficking, vessel growth, and hemostasis (1Griendling K.K. Alexander R.W. FASEB J. 1996; 10: 283-292Crossref PubMed Scopus (134) Google Scholar). In particular, the vascular endothelium modulates vascular tone and blood pressure through the coordinated production of potent vasoactive molecules. In addition, the endothelium directs formation of the vascular system during development through its role in the processes of vasculogenesis (development of blood vessels from angioblasts in situ) andangiogenesis (sprouting of new vessels from existing vessels) (2Risau W. Flamme I. Annu. Rev. Cell Dev. Biol. 1995; 11: 73-91Crossref PubMed Scopus (1337) Google Scholar). Whereas endothelial mechanisms during development and in adulthood may seem discrete, there is now strong evidence that they overlap considerably, and that molecules required for normal vascular development may contribute to vascular homeostasis in adulthood, and vice versa. Endothelin-1 (ET-1),1 a 21-amino acid peptide originally isolated from porcine endothelial cells (3Yanagisawa M. Kurihara H. Kimura S. Tomobe Y. Kobayashi M. Mitsui Y. Yazaki Y. Goto K. Masaki T. Nature. 1988; 332: 411-415Crossref PubMed Scopus (10185) Google Scholar), provides one example of an endothelial cell protein that is critical both for cardiovascular development in the embryo and for vascular homeostasis in the adult. ET-1, which is expressed primarily in endothelial cells and also epithelial cells of the branchial arches during development (4Thomas T. Kurihara H. Yamagishi H. Kurihara Y. Yazaki Y. Olson E.N. Srivastava D. Development. 1998; 125: 3005-3014PubMed Google Scholar), is required for the development of neural crest-derived tissues arising from the branchial arches, such as the great vessels, the ventricular septum, and craniofacial structures (5Kurihara Y. Kurihara H. Oda H. Maemura K. Nagai R. Ishikawa T. Yazaki Y. J. Clin. Invest. 1995; 96: 293-300Crossref PubMed Scopus (331) Google Scholar). These effects seem to be mediated via interactions with the endothelin-A receptor, which is expressed in neural crest cells. Loss of ET-1 signaling leads to apoptosis of post-migratory neural crest-derived mesenchymal cells, with resultant cardiovascular defects such as ventricular septal defects, truncus arteriosus, and interruption of the aortic arch. In addition to its function as a critical developmental signal for the cardiovascular system, ET-1 has potent and complex effects on the adult vasculature. ET-1 has direct vasoconstrictor effects on vascular smooth muscle cells, and sensitizes smooth muscle cells to the effects of angiotensin II and norepinephrine (6Miller W.L. Redfield M.M. Burnett J.C. J. Clin. Invest. 1989; 83: 317-320Crossref PubMed Scopus (497) Google Scholar). ET-1 also stimulates the release of aldosterone and nitric oxide, the latter effect indicating that the vasoconstrictor effects of ET-1 may be most pronounced when endothelial function is compromised. The effects of ET-1 are linked pathophysiologically to the development of hypertension, cardiac hypertrophy (7Ito H. Hirata Y. Hiroe M. Tsujino M. Adachi S. Takamoto T. Nitta M. Taniguchi K. Marumo F. Circ. Res. 1991; 69: 209-215Crossref PubMed Scopus (460) Google Scholar), and ischemic heart disease (8Serneri G.G. Cecioni I. Vanni S. Paniccia R. Bandinelli B. Vetere A. Janming X. Bertolozzi I. Boddi M. Lisi G.F. Sani G. Modesti P.A. Circ. Res. 2000; 86: 377-385Crossref PubMed Google Scholar). Given the bifunctional role of ET-1 in development and in vascular homeostasis, it is not surprising that its expression and activity are tightly regulated at the transcriptional level. The humanET-1 gene has a TATA box-containing promoter, and severalcis-acting elements have been implicated in transcriptional regulation of ET-1 mRNA. An upstream activator protein-1 (AP-1) site located at position −117, which is bound by c-fos and c-jun, is required for inducible high-level ET-1 promoter activity (9Lee M.E. Dhadly M.S. Temizer D.H. Clifford J.A. Yoshizumi M. Quertermous T. J. Biol. Chem. 1991; 266: 19034-19039Abstract Full Text PDF PubMed Google Scholar). In addition, a GATA motif at position −135, which is bound by the zinc finger transcription factor GATA-2 in endothelial cells (10Lee M.E. Temizer D.H. Clifford J.A. Quertermous T. J. Biol. Chem. 1991; 266: 16188-16192Abstract Full Text PDF PubMed Google Scholar), is crucial to the basal and regulated expression of the ET-1 gene. Furthermore, the cooperativity between the AP-1 complex and GATA-2 leads to a synergistic increase in trans-activation ofET-1 (11Kawana M. Lee M. Quertermous E. Quertermous T. Mol. Cell. Biol. 1995; 15: 42256-44231Crossref Scopus (178) Google Scholar). Last, hypoxia-mediated expression of ET-1 is mediated via trans-activation of the ET-1promoter by hypoxia-inducible factor-1 (HIF-1) (12Yamashita K. Discher D.J. Hu J. Bishopric N.H. Webster K.A. J. Biol. Chem. 2001; 276: 12645-12653Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar). However, the expression of fos/jun and GATA-2 is not restricted to endothelial cells, and the up-regulation of theET-1 gene via the GATA motif is not limited to GATA-2, as other members of the GATA family, such as GATA-1 and GATA-3, exert a similar effect (11Kawana M. Lee M. Quertermous E. Quertermous T. Mol. Cell. Biol. 1995; 15: 42256-44231Crossref Scopus (178) Google Scholar). Because GATA-2, HIF-1, and the Fos and Jun family members are expressed more promiscuously than is ET-1, the action of these factors alone cannot be responsible for the cell type-restricted activation of the ET-1 gene. Therefore, it is possible that the binding of the trans-acting factors to these sites may recruit or otherwise cooperate with additional proteins which are important for cell restricted expression of theET-1 gene. In any event, a 6-kilobase fragment of the mouse ET-" @default.
• W2080371298 created "2016-06-24" @default.
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• W2080371298 creator A5017927459 @default.
• W2080371298 creator A5047456289 @default.
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• W2080371298 date "2001-10-01" @default.
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• W2080371298 title "Vezf1/DB1 Is an Endothelial Cell-specific Transcription Factor That Regulates Expression of the Endothelin-1 Promoter" @default.
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