Genomic Organization of Human and Mouse Genes for Vascular Endothelial Growth Factor C

Abstract

We report here the cloning and characterization of human and mouse genes for vascular endothelial growth factor C (VEGF-C), a newly isolated member of the vascular endothelial growth factor/platelet-derived growth factor (VEGF/PDGF) family. Both VEGF-C genes comprise over 40 kilobase pairs of genomic DNA and consist of seven exons, all containing coding sequences. The VEGF homology domain of VEGF-C is encoded by exons 3 and 4. Exons 5 and 7 encode cysteine-rich motifs of the type C6C10CRC, and exon 6 encodes additional C10CXCXC motifs typical of a silk protein. A putative alternatively spliced rare RNA form lacking exon 4 was identified in human fibrosarcoma cells, and a major transcription start site was located in the human VEGF-C gene 523 base pairs upstream of the translation initiation codon. The upstream promoter sequences contain conserved putative binding sites for Sp-1, AP-2, and NF-κB transcription factors but no TATA box, and they show promoter activity when transfected into cells. The VEGF-C gene structure is thus assembled from exons encoding propeptides and distinct cysteine-rich domains in addition to the VEGF homology domain, and it shows both similarities and distinct differences in comparison with other members of the VEGF/PDGF gene family. We report here the cloning and characterization of human and mouse genes for vascular endothelial growth factor C (VEGF-C), a newly isolated member of the vascular endothelial growth factor/platelet-derived growth factor (VEGF/PDGF) family. Both VEGF-C genes comprise over 40 kilobase pairs of genomic DNA and consist of seven exons, all containing coding sequences. The VEGF homology domain of VEGF-C is encoded by exons 3 and 4. Exons 5 and 7 encode cysteine-rich motifs of the type C6C10CRC, and exon 6 encodes additional C10CXCXC motifs typical of a silk protein. A putative alternatively spliced rare RNA form lacking exon 4 was identified in human fibrosarcoma cells, and a major transcription start site was located in the human VEGF-C gene 523 base pairs upstream of the translation initiation codon. The upstream promoter sequences contain conserved putative binding sites for Sp-1, AP-2, and NF-κB transcription factors but no TATA box, and they show promoter activity when transfected into cells. The VEGF-C gene structure is thus assembled from exons encoding propeptides and distinct cysteine-rich domains in addition to the VEGF homology domain, and it shows both similarities and distinct differences in comparison with other members of the VEGF/PDGF gene family. The process of growth and development of new blood vessels from preexisting ones is termed angiogenesis. Angiogenesis plays a critical role in providing growing tissues with oxygen and nutrients and also occurs in some pathological conditions, including tumor growth and metastasis, inflammatory lesions, wound healing, and endocrine diseases (1Folkman J. Nature Medicine. 1995; 1: 27-31Crossref PubMed Scopus (7176) Google Scholar). Specific growth factors for the vascular endothelium, namely vascular endothelial growth factor (VEGF), 1The abbreviations used are: VEGF, vascular endothelial growth factor; PlGF, placenta growth factor; PDGF, platelet-derived growth factor; VEGFR, vascular endothelial growth factor receptor; bp, base pair(s); kb, kilobase pair(s); PCR, polymerase chain reaction; RT-PCR, reverse transcriptase-polymerase chain reaction.1The abbreviations used are: VEGF, vascular endothelial growth factor; PlGF, placenta growth factor; PDGF, platelet-derived growth factor; VEGFR, vascular endothelial growth factor receptor; bp, base pair(s); kb, kilobase pair(s); PCR, polymerase chain reaction; RT-PCR, reverse transcriptase-polymerase chain reaction. VEGF-B, VEGF-C, and placenta growth factor (PlGF) form a subfamily of the platelet-derived growth factor family (2Ferrara N. Davis-Smyth T. Endocr. Rev. 1997; 18: 4-25Crossref PubMed Scopus (3668) Google Scholar, 3Neufeld G. Tessler S. Gitay-Goren H. Cohen T. Levi B.-Z. Prog. Growth Factor Res. 1994; 5: 89-97Abstract Full Text PDF PubMed Scopus (210) Google Scholar, 4Dvorak H.F. Brown L.F. Detmar M. Dvorak A.M. Am. J. Pathol. 1995; 146: 1029-1039PubMed Google Scholar, 5Klagsburn M. D'Amore P.A. Cytokine Growth Factor Rev. 1996; 7: 259-270Crossref PubMed Scopus (401) Google Scholar). Certain other angiogenic growth factors may also act indirectly on endothelial cells via the induction of VEGF secretion in adjacent cells (4Dvorak H.F. Brown L.F. Detmar M. Dvorak A.M. Am. J. Pathol. 1995; 146: 1029-1039PubMed Google Scholar, 6Pertovaara L. Kaipainen A. Mustonen T. Orpana A. Ferrara N. Saksela O. Alitalo K. J. Biol. Chem. 1994; 269: 6271-6274Abstract Full Text PDF PubMed Google Scholar). Besides angiogenesis, VEGF is implicated in vasculogenesis or formation of blood vessels de novo by in situ differentiation from mesodermal precursor cells (7Risau W. Sariola H. Zerwes H.-G. Sasse J. Ekblom P. Kemler R. Doetschman T. Development. 1988; 102: 471-478PubMed Google Scholar). Both vasculogenesis and angiogenesis appear to be further regulated by inhibitory signals from cells and pericellular matrices (8Folkman J. Shing Y. J. Biol. Chem. 1992; 267: 10931-10934Abstract Full Text PDF PubMed Google Scholar, 9Hanahan D. Folkman J. Cell. 1996; 86: 353-364Abstract Full Text Full Text PDF PubMed Scopus (6016) Google Scholar).In situ hybridization studies have revealed that the three VEGF receptors VEGFR-1 (Flt-1), VEGFR-2 and have in tissues A. J. K. O. Alitalo K. J. PubMed Scopus Google Scholar). in blood in the of vessels the A. J. Mustonen T. D. M. Alitalo K. S. A. 1995; PubMed Scopus Google Scholar). in the of tissues that it a of the of VEGF-C is in tissues the vessels A. S. Kaipainen A. M. Alitalo K. Development. 1996; Google and of VEGF-C in M. Kaipainen A. M. H. R. Alitalo K. 1997; PubMed Scopus Google sequences of the growth factor family by conserved the of PDGF, the have to be for the and of the M. A. G. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar, A. M. J. 1992; PubMed Scopus Google activity was when the M. T. J. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar). The VEGF-C consist of of and by of the precursor and and via further G. S. R. S. T. J. 1997; PubMed Scopus Google Scholar, K. Kaipainen A. D. Saksela O. N. Alitalo K. J. 1996; PubMed Scopus Google Scholar, T. M. L. Y. Saksela O. N. Alitalo K. J. 1997; PubMed Scopus Google Scholar). C the VEGF-C precursor a domain of sequences of a silk protein. VEGF/PDGF family members have of encoded by alternatively spliced and VEGF binding to S. H. G. M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google and characterization of the VEGF gene promoter from and mouse S. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, R. T. M. D. J. Biol. Chem. Full Text PDF PubMed Google Scholar, M. D'Amore P.A. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The human promoter was to contain binding sites for Sp-1, and transcription factors and S. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, R. T. M. D. J. Biol. Chem. Full Text PDF PubMed Google Scholar, M. D'Amore P.A. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). promoter is and to including tumor and growth factor M. M. H. S. K. M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). A of the mouse VEGF gene promoter activity S. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, M. D'Amore P.A. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). the promoter also a VEGF gene induction by is also via J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google report here the cloning and characterization of the human and mouse VEGF-C The genomic structure of the VEGF-C gene and alternatively spliced human is We show that human genomic containing the transcription initiation site for promoter activity in transfected is the member of the VEGF subfamily of growth factors and the VEGF gene The genomic of the VEGF, VEGF-B, and show a of other in and some similarities of the of VEGF-C, the exon structure that of the other VEGF family in exons 3 and 4 encoding the growth factor domain, the and the conserved in all family The of genes the encoded by the and exons, alternatively spliced in all other members A exon is in all of the other but VEGF-C to is a in the sequences encoded by exon 4. to exon encodes of a binding domain in and is in VEGF-C R. T. M. D. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Cohen T. R. Y. G. G. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google have a cysteine-rich C the of VEGF-C, the cysteine-rich domain is in a and into three Exons show no homology with VEGF, the encoded by exons 5 and 7 of VEGF-C may be to the in exons 7 and of VEGF R. T. M. D. J. Biol. Chem. Full Text PDF PubMed Google and and 7 of J. S. M. G. Res. 1996; PubMed Scopus Google K. Kaipainen A. G. Saksela O. Orpana A. R. Alitalo K. S. A. 1996; PubMed Scopus Google Scholar). The of domains in the VEGF-C gene to some that of the the and propeptides also 5: Full Text PDF PubMed Scopus Google differences VEGF-C and the other the We have hybridization of of and with the VEGF-C J. A. J. H. S. A. 1996; PubMed Scopus Google VEGF-C containing of or to exon 4 or exons to be the of We report here a alternatively spliced of VEGF-C lacking exon 4. of exon 4 in a by a the of exon contain the site and of the precursor and of the conserved of the VEGF homology domain K. Kaipainen A. D. Saksela O. N. Alitalo K. J. 1996; PubMed Scopus Google Scholar). a of the was from a containing the but in have to show that is of the of S. M. J. A. and of VEGF structure have that the the binding sites and in and Y. H. J. A. S. A. 1997; PubMed Scopus Google Scholar). of the contain of the protein. that the and cells tissues major form of the alternatively spliced in the may a rare that is to have in the cells and tissues A was from of the mouse VEGF-C coding transcription of the human VEGF-C gene 523 the coding the a for the VEGF gene R. T. M. D. J. Biol. Chem. Full Text PDF PubMed Google the VEGF-C gene promoter TATA and sequences. it putative binding sites for Sp-1, a that transcription from genes R. Cell. Full Text PDF PubMed Scopus Google and a is typical for growth factor genes and is to have a role in R. T. M. D. J. Biol. Chem. Full Text PDF PubMed Google M. D'Amore P.A. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. 1988; PubMed Scopus Google Scholar, H. K. PubMed Scopus Google Scholar). sequences upstream of the VEGF-C translation start site to contain binding sites for the transcription that the and of the transcription factor VEGF-C transcription M. R. M. Cell. Full Text PDF PubMed Scopus Google Scholar, J. R. S. J. 1997; PubMed Scopus Google Scholar, R. Cell. Full Text PDF PubMed Scopus Google Scholar). have here that the VEGF-C promoter activity is by The was in cells, some of be to K. A. Y. J. L. M. Alitalo K. 1997; PubMed Scopus Google Scholar). may be located of the promoter used in the for in the of binding site for the NF-κB transcription factor for the and was also NF-κB is with and is to be by a of inflammatory a of gene P.A. D. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, D. Cell. Full Text PDF PubMed Scopus Google Scholar). The of NF-κB sites that NF-κB may be implicated in the induction of the VEGF-C by and tumor D. S. M. J. A. and the VEGF the VEGF-C gene promoter contain putative binding sites for studies have that major for the induction of the VEGF gene is the of the of S. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, D. A. D. 1992; PubMed Scopus Google Scholar, J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The VEGF is to be by the of motifs in M. D'Amore P.A. Cytokine Growth Factor Rev. 1996; 7: 259-270Crossref PubMed Scopus (401) Google Scholar, J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The of the VEGF-C gene also a of but that the by the differences in exon structure and encoded the VEGF-C gene also differences in and in comparison with the VEGF of gene family M. Kaipainen A. M. H. R. Alitalo K. 1997; PubMed Scopus Google Scholar, K. A. Y. J. L. M. Alitalo K. 1997; PubMed Scopus Google Scholar). into the sequences for the of for the newly is with human VEGF-C and with human VEGF M. L. R. S. S. A. 1996; PubMed Scopus Google Scholar, D. G. O. Alitalo K. G. Google Scholar). the of VEGF-C and to have and and gene the and genes have from and from from other The process of growth and development of new blood vessels from preexisting ones is termed angiogenesis. Angiogenesis plays a critical role in providing growing tissues with oxygen and nutrients and also occurs in some pathological conditions, including tumor growth and metastasis, inflammatory lesions, wound healing, and endocrine diseases (1Folkman J. Nature Medicine. 1995; 1: 27-31Crossref PubMed Scopus (7176) Google Scholar). Specific growth factors for the vascular endothelium, namely vascular endothelial growth factor (VEGF), 1The abbreviations used are: VEGF, vascular endothelial growth factor; PlGF, placenta growth factor; PDGF, platelet-derived growth factor; VEGFR, vascular endothelial growth factor receptor; bp, base pair(s); kb, kilobase pair(s); PCR, polymerase chain reaction; RT-PCR, reverse transcriptase-polymerase chain reaction.1The abbreviations used are: VEGF, vascular endothelial growth factor; PlGF, placenta growth factor; PDGF, platelet-derived growth factor; VEGFR, vascular endothelial growth factor receptor; bp, base pair(s); kb, kilobase pair(s); PCR, polymerase chain reaction; RT-PCR, reverse transcriptase-polymerase chain reaction. VEGF-B, VEGF-C, and placenta growth factor (PlGF) form a subfamily of the platelet-derived growth factor family (2Ferrara N. Davis-Smyth T. Endocr. Rev. 1997; 18: 4-25Crossref PubMed Scopus (3668) Google Scholar, 3Neufeld G. Tessler S. Gitay-Goren H. Cohen T. Levi B.-Z. Prog. Growth Factor Res. 1994; 5: 89-97Abstract Full Text PDF PubMed Scopus (210) Google Scholar, 4Dvorak H.F. Brown L.F. Detmar M. Dvorak A.M. Am. J. Pathol. 1995; 146: 1029-1039PubMed Google Scholar, 5Klagsburn M. D'Amore P.A. Cytokine Growth Factor Rev. 1996; 7: 259-270Crossref PubMed Scopus (401) Google Scholar). Certain other angiogenic growth factors may also act indirectly on endothelial cells via the induction of VEGF secretion in adjacent cells (4Dvorak H.F. Brown L.F. Detmar M. Dvorak A.M. Am. J. Pathol. 1995; 146: 1029-1039PubMed Google Scholar, 6Pertovaara L. Kaipainen A. Mustonen T. Orpana A. Ferrara N. Saksela O. Alitalo K. J. Biol. Chem. 1994; 269: 6271-6274Abstract Full Text PDF PubMed Google Scholar). Besides angiogenesis, VEGF is implicated in vasculogenesis or formation of blood vessels de novo by in situ differentiation from mesodermal precursor cells (7Risau W. Sariola H. Zerwes H.-G. Sasse J. Ekblom P. Kemler R. Doetschman T. Development. 1988; 102: 471-478PubMed Google Scholar). Both vasculogenesis and angiogenesis appear to be further regulated by inhibitory signals from cells and pericellular matrices (8Folkman J. Shing Y. J. Biol. Chem. 1992; 267: 10931-10934Abstract Full Text PDF PubMed Google Scholar, 9Hanahan D. Folkman J. Cell. 1996; 86: 353-364Abstract Full Text Full Text PDF PubMed Scopus (6016) Google Scholar). situ hybridization studies have revealed that the three VEGF receptors VEGFR-1 (Flt-1), VEGFR-2 and have in tissues A. J. K. O. Alitalo K. J. PubMed Scopus Google Scholar). in blood in the of vessels the A. J. Mustonen T. D. M. Alitalo K. S. A. 1995; PubMed Scopus Google Scholar). in the of tissues that it a of the of VEGF-C is in tissues the vessels A. S. Kaipainen A. M. Alitalo K. Development. 1996; Google and of VEGF-C in M. Kaipainen A. M. H. R. Alitalo K. 1997; PubMed Scopus Google Scholar). sequences of the growth factor family by conserved the of PDGF, the have to be for the and of the M. A. G. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar, A. M. J. 1992; PubMed Scopus Google activity was when the M. T. J. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar). The VEGF-C consist of of and by of the precursor and and via further G. S. R. S. T. J. 1997; PubMed Scopus Google Scholar, K. Kaipainen A. D. Saksela O. N. Alitalo K. J. 1996; PubMed Scopus Google Scholar, T. M. L. Y. Saksela O. N. Alitalo K. J. 1997; PubMed Scopus Google Scholar). C the VEGF-C precursor a domain of sequences of a silk protein. VEGF/PDGF family members have of encoded by alternatively spliced and VEGF binding to S. H. G. M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The and characterization of the VEGF gene promoter from and mouse S. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, R. T. M. D. J. Biol. Chem. Full Text PDF PubMed Google Scholar, M. D'Amore P.A. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The human promoter was to contain binding sites for Sp-1, and transcription factors and S. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, R. T. M. D. J. Biol. Chem. Full Text PDF PubMed Google Scholar, M. D'Amore P.A. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). promoter is and to including tumor and growth factor M. M. H. S. K. M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). A of the mouse VEGF gene promoter activity S. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, M. D'Amore P.A. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). the promoter also a VEGF gene induction by is also via J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). We report here the cloning and characterization of the human and mouse VEGF-C The genomic structure of the VEGF-C gene and alternatively spliced human is We show that human genomic containing the transcription initiation site for promoter activity in transfected cells. is the member of the VEGF subfamily of growth factors and the VEGF gene The genomic of the VEGF, VEGF-B, and show a of other in and some similarities of the of VEGF-C, the exon structure that of the other VEGF family in exons 3 and 4 encoding the growth factor domain, the and the conserved in all family The of genes the encoded by the and exons, alternatively spliced in all other members A exon is in all of the other but VEGF-C to is a in the sequences encoded by exon 4. to exon encodes of a binding domain in and is in VEGF-C R. T. M. D. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Cohen T. R. Y. G. G. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google have a cysteine-rich C the of VEGF-C, the cysteine-rich domain is in a and into three Exons show no homology with VEGF, the encoded by exons 5 and 7 of VEGF-C may be to the in exons 7 and of VEGF R. T. M. D. J. Biol. Chem. Full Text PDF PubMed Google and and 7 of J. S. M. G. Res. 1996; PubMed Scopus Google K. Kaipainen A. G. Saksela O. Orpana A. R. Alitalo K. S. A. 1996; PubMed Scopus Google Scholar). The of domains in the VEGF-C gene to some that of the the and propeptides also 5: Full Text PDF PubMed Scopus Google differences VEGF-C and the other the We have hybridization of of and with the VEGF-C J. A. J. H. S. A. 1996; PubMed Scopus Google VEGF-C containing of or to exon 4 or exons to be the of We report here a alternatively spliced of VEGF-C lacking exon 4. of exon 4 in a by a the of exon contain the site and of the precursor and of the conserved of the VEGF homology domain K. Kaipainen A. D. Saksela O. N. Alitalo K. J. 1996; PubMed Scopus Google Scholar). a of the was from a containing the but in have to show that is of the of S. M. J. A. and of VEGF structure have that the the binding sites and in and Y. H. J. A. S. A. 1997; PubMed Scopus Google Scholar). of the contain of the protein. that the and cells tissues major form of the alternatively spliced in the may a rare that is to have in the cells and tissues A was from of the mouse VEGF-C coding transcription of the human VEGF-C gene 523 the coding the a for the VEGF gene R. T. M. D. J. Biol. Chem. Full Text PDF PubMed Google the VEGF-C gene promoter TATA and sequences. it putative binding sites for Sp-1, a that transcription from genes R. Cell. Full Text PDF PubMed Scopus Google and a is typical for growth factor genes and is to have a role in R. T. M. D. J. Biol. Chem. Full Text PDF PubMed Google M. D'Amore P.A. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. 1988; PubMed Scopus Google Scholar, H. K. PubMed Scopus Google Scholar). sequences upstream of the VEGF-C translation start site to contain binding sites for the transcription that the and of the transcription factor VEGF-C transcription M. R. M. Cell. Full Text PDF PubMed Scopus Google Scholar, J. R. S. J. 1997; PubMed Scopus Google Scholar, R. Cell. Full Text PDF PubMed Scopus Google Scholar). have here that the VEGF-C promoter activity is by The was in cells, some of be to K. A. Y. J. L. M. Alitalo K. 1997; PubMed Scopus Google Scholar). may be located of the promoter used in the for in the of binding site for the NF-κB transcription factor for the and was also NF-κB is with and is to be by a of inflammatory a of gene P.A. D. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, D. Cell. Full Text PDF PubMed Scopus Google Scholar). The of NF-κB sites that NF-κB may be implicated in the induction of the VEGF-C by and tumor D. S. M. J. A. and the VEGF the VEGF-C gene promoter contain putative binding sites for studies have that major for the induction of the VEGF gene is the of the of S. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, D. A. D. 1992; PubMed Scopus Google Scholar, J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The VEGF is to be by the of motifs in M. D'Amore P.A. Cytokine Growth Factor Rev. 1996; 7: 259-270Crossref PubMed Scopus (401) Google Scholar, J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The of the VEGF-C gene also a of but that the by the differences in exon structure and encoded the VEGF-C gene also differences in and in comparison with the VEGF of gene family M. Kaipainen A. M. H. R. Alitalo K. 1997; PubMed Scopus Google Scholar, K. A. Y. J. L. M. Alitalo K. 1997; PubMed Scopus Google Scholar). into the sequences for the of for the newly is with human VEGF-C and with human VEGF M. L. R. S. S. A. 1996; PubMed Scopus Google Scholar, D. G. O. Alitalo K. G. Google Scholar). the of VEGF-C and to have and and gene the and genes have from and from from other VEGF-C is the member of the VEGF subfamily of growth factors and the VEGF gene The genomic of the VEGF, VEGF-B, and show a of other in and some similarities of the of VEGF-C, the exon structure that of the other VEGF family in exons 3 and 4 encoding the growth factor domain, the and the conserved in all family The of genes the encoded by the and exons, alternatively spliced in all other members A exon is in all of the other but VEGF-C to is a in the sequences encoded by exon 4. to exon encodes of a binding domain in and is in VEGF-C R. T. M. D. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Cohen T. R. Y. G. G. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). have a cysteine-rich C the of VEGF-C, the cysteine-rich domain is in a and into three Exons show no homology with VEGF, the encoded by exons 5 and 7 of VEGF-C may be to the in exons 7 and of VEGF R. T. M. D. J. Biol. Chem. Full Text PDF PubMed Google and and 7 of J. S. M. G. Res. 1996; PubMed Scopus Google K. Kaipainen A. G. Saksela O. Orpana A. R. Alitalo K. S. A. 1996; PubMed Scopus Google Scholar). The of domains in the VEGF-C gene to some that of the the and propeptides also 5: Full Text PDF PubMed Scopus Google Scholar). The differences VEGF-C and the other the We have hybridization of of and with the VEGF-C J. A. J. H. S. A. 1996; PubMed Scopus Google VEGF-C containing of or to exon 4 or exons to be the of We report here a alternatively spliced of VEGF-C lacking exon 4. of exon 4 in a by a the of exon contain the site and of the precursor and of the conserved of the VEGF homology domain K. Kaipainen A. D. Saksela O. N. Alitalo K. J. 1996; PubMed Scopus Google Scholar). a of the was from a containing the but in have to show that is of the of S. M. J. A. and of VEGF structure have that the the binding sites and in and Y. H. J. A. S. A. 1997; PubMed Scopus Google Scholar). of the contain of the protein. that the and cells tissues major form of the alternatively spliced in the may a rare that is to have in the cells and tissues A was from of the mouse VEGF-C coding The transcription of the human VEGF-C gene 523 the coding the a for the VEGF gene R. T. M. D. J. Biol. Chem. Full Text PDF PubMed Google the VEGF-C gene promoter TATA and sequences. it putative binding sites for Sp-1, a that transcription from genes R. Cell. Full Text PDF PubMed Scopus Google and a is typical for growth factor genes and is to have a role in R. T. M. D. J. Biol. Chem. Full Text PDF PubMed Google M. D'Amore P.A. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. 1988; PubMed Scopus Google Scholar, H. K. PubMed Scopus Google Scholar). sequences upstream of the VEGF-C translation start site to contain binding sites for the transcription that the and of the transcription factor VEGF-C transcription M. R. M. Cell. Full Text PDF PubMed Scopus Google Scholar, J. R. S. J. 1997; PubMed Scopus Google Scholar, R. Cell. Full Text PDF PubMed Scopus Google Scholar). have here that the VEGF-C promoter activity is by The was in cells, some of be to K. A. Y. J. L. M. Alitalo K. 1997; PubMed Scopus Google Scholar). may be located of the promoter used in the for in the of binding site for the NF-κB transcription factor for the and was also NF-κB is with and is to be by a of inflammatory a of gene P.A. D. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, D. Cell. Full Text PDF PubMed Scopus Google Scholar). The of NF-κB sites that NF-κB may be implicated in the induction of the VEGF-C by and tumor D. S. M. J. A. and the VEGF the VEGF-C gene promoter contain putative binding sites for studies have that major for the induction of the VEGF gene is the of the of S. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, D. A. D. 1992; PubMed Scopus Google Scholar, J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The VEGF is to be by the of motifs in M. D'Amore P.A. Cytokine Growth Factor Rev. 1996; 7: 259-270Crossref PubMed Scopus (401) Google Scholar, J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The of the VEGF-C gene also a of but that the by the differences in exon structure and encoded the VEGF-C gene also differences in and in comparison with the VEGF of gene family M. Kaipainen A. M. H. R. Alitalo K. 1997; PubMed Scopus Google Scholar, K. A. Y. J. L. M. Alitalo K. 1997; PubMed Scopus Google Scholar). into the sequences for the of for the newly is with human VEGF-C and with human VEGF M. L. R. S. S. A. 1996; PubMed Scopus Google Scholar, D. G. O. Alitalo K. G. Google Scholar). the of VEGF-C and to have and and gene the and genes have from and from from other We and for