The human VE-cadherin promoter is subjected to organ-specific regulation and is activated in tumour angiogenesis.
Vascular endothelial (VE)-cadherin is exclusively expressed at interendothelial junctions of normal and tumour vessels. In this report, we characterized the transcriptional activity of the human VE-cadherin promoter. Transient transfection assays revealed that sequences at positions --1135/-744 and -166/-5 base pairs are critical for promoter activity in endothelial cells. We show that specific sequences in the proximal region interact with Ets and Sp1 family members. Transgenic mice were created and the human VE-cadherin promoter was able to confer correct temporal and spatial expression on the LacZ gene in embryos. In adults, the transgene was specifically and strongly expressed in the lung, heart, ovary, spleen and kidney glomeruli, whereas expression was weak or absent in the vasculature of other organs, including the brain, thymus, liver and skeletal muscle. Neovessels in tumour grafts and Matrigel implants harboured strong stainings, indicating that promoter activity is enhanced in angiogenic situations. Furthermore, Matrigel and transfection assays showed that VE-cadherin promoter is subjected to bFGF induction. Transgene expression was also noticed in extravascular sites of the central nervous system, suggesting that silencer elements may be located elsewhere in the gene. These results are a first step towards addressing the organ- and tumour-specific regulation of the VE-cadherin gene.
Prandini
Marie-Hélène
MH
Department of Cellular Responses and Dynamics, CEA-INSERM-Joseph Fourier University EMI 0219, CEA-Grenoble, France.
Dreher
Inge
I
Bouillot
Stéphanie
S
Benkerri
Souhila
S
Moll
Thomas
T
Huber
Philippe
P
D000818:Animals; D015703:Antigens, CD; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D000099152:Cadherin 5
J Cell Biol. 1997 Oct 6;139(1):257-64
9314544
Lab Invest. 1992 Oct;67(4):519-28
1279270
Anticancer Res. 2002 Mar-Apr;22(2A):605-12
12014628
J Biol Chem. 1995 Jul 28;270(30):17908-12
7629096
Cancer Res. 2002 May 1;62(9):2567-75
11980651
Nucleic Acids Res. 1995 Dec 11;23(23):4878-84
8532532
J Biol Chem. 1998 Mar 20;273(12):6750-5
9506975
Development. 1998 May;125(9):1747-57
9521912
Proc Natl Acad Sci U S A. 1988 Apr;85(8):2603-7
3128790
Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9815-20
10449777
Am J Physiol. 1999 Feb;276(2 Pt 2):H736-48
9950877
Am J Physiol Lung Cell Mol Physiol. 2000 Dec;279(6):L1218-25
11076812
Oncogene. 2003 Mar 27;22(12):1795-806
12660815
Genomics. 1996 Feb 15;32(1):21-8
8786117
Blood. 1999 Jan 1;93(1):184-92
9864160
Neoplasia. 2000 Nov-Dec;2(6):531-9
11228546
J Cell Biochem. 1999 Jun 1;73(3):408-22
10321840
Gene Ther. 2003 Jul;10(14):1170-8
12833126
J Cell Biol. 1992 Sep;118(6):1511-22
1522121
Development. 1999 May;126(10):2093-102
10207135
Arterioscler Thromb Vasc Biol. 1995 Aug;15(8):1229-39
7627717
J Cell Biol. 1997 Sep 8;138(5):1117-24
9281588
Arterioscler Thromb Vasc Biol. 2003 May 1;23(5):748-54
12676798
J Cell Sci. 1999 Jun;112 ( Pt 12):1915-23
10341210
Circ Res. 1997 Oct;81(4):457-61
9314825
Oncogene. 2002 Aug 12;21(35):5388-93
12154401
Mol Cell Endocrinol. 2002 Mar 28;189(1-2):85-96
12039067
Gene. 2001 Nov 14;279(1):49-62
11722845
Biol Chem. 2002 Jun;383(6):893-906
12222679
Eur J Cell Biol. 1994 Apr;63(2):247-54
8082649
Cell. 1996 Feb 9;84(3):345-57
8608588
J Biol Chem. 1998 Nov 6;273(45):29786-93
9792693
J Clin Invest. 1998 Jul 15;102(2):430-7
9664085
Nature. 2000 Sep 14;407(6801):249-57
11001068
Cytometry. 1991;12(4):291-301
1905992
Trends Immunol. 2002 Aug;23(8):375-8
12133792
Cell. 1999 Jul 23;98(2):147-57
10428027
J Biol Chem. 2002 Jul 5;277(27):24014-21
11978792
J Biol Chem. 2003 May 30;278(22):19909-16
12456679
Blood. 2001 Mar 15;97(6):1679-84
11238107
Nat Med. 2003 Jun;9(6):661-8
12778164
Circ Res. 2001 Feb 2;88(2):167-74
11157668
Trends Mol Med. 2002 Dec;8(12):563-71
12470989
Biochim Biophys Acta. 2002 Sep 27;1577(3):384-94
12359328
Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7291-5
8041783
J Cell Sci. 1997 Mar;110 ( Pt 5):583-8
9092940
Circ Res. 1999 Sep 17;85(6):479-88
10488050
EMBO J. 1999 Jul 15;18(14):3964-72
10406801
J Biol Chem. 2003 May 2;278(18):16230-6
12595527
Nat Rev Genet. 2002 May;3(5):370-9
11988762
J Mol Biol. 1981 Mar 25;147(1):195-7
7265238
Blood. 1996 Jan 15;87(2):630-41
8555485
Blood. 2002 Aug 1;100(3):905-11
12130501