Wilms' tumour protein Wt1 stimulates transcription of the gene encoding vascular endothelial cadherin.
The Wilms' tumour gene, Wt1, encodes a zinc finger protein, which is mutated in a subset of paediatric renal carcinomas known as Wilms' tumours (nephroblastomas). Recent findings indicate that Wt1, beside its role in genitourinary development, is also necessary for normal vascularisation of the embryonic heart, and may even be involved in tumour angiogenesis. The original purpose of this study was to decipher potential downstream signalling pathways of Wt1 for blood vessel formation. We found that the Wt1(-KTS) protein, which functions as a transcription factor, stimulated the expression of cadherin 5 (CDH5, vascular endothelial (VE) cadherin) and other vascular genes, i.e. those encoding vascular endothelial growth factor receptors 1 and 2, and angiopoietin-2. Furthermore, an enhancer element was identified in the first intron of the CDH5 gene, which bound to the Wt1(-KTS) protein and was necessary for reporter gene activation by Wt1(-KTS) in transiently transfected cell lines. Wt1 and VE-cadherin proteins could be co-localised by double immunofluorescence staining in maturating glomeruli of embryonic murine kidneys. VE-cadherin transcripts were reduced in some but not all tissues of Wt1-deficient mouse embryos. These results indicate that Wt1 can stimulate vascular gene transcription. By demonstrating that Wt1(-KTS) protein trans-activates an enhancer element in the first intron we identified CDH5 as a novel target gene of Wt1. It is suggested that transcriptional activation of CDH5 by Wt1 fulfils regulatory functions during vascular development and kidney formation.
Kirschner
Karin M
KM
Institut für Vegetative Physiologie, Charité - Universitätsmedizin Berlin, 10115 Berlin, Germany.
Sciesielski
Lina K
LK
Scholz
Holger
H
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D001483:Base Sequence; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic / Q000502:physiology; D006321:Heart / Q000196:embryology; D006801:Humans; D007678:Kidney Glomerulus / Q000196:embryology; D008099:Liver / Q000196:embryology; D051379:Mice; D008969:Molecular Sequence Data; D012516:Osteosarcoma / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D025721:WT1 Proteins / Q000172:deficiency / Q000502:physiology*; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D012333:RNA, Messenger; D025721:WT1 Proteins; D000099152:Cadherin 5
Cell. 1993 Aug 27;74(4):679-91
8395349
Mamm Genome. 2000 Nov;11(11):1030-3
11063261
Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5682-7
16581909
Biochim Biophys Acta. 2008 Jan;1785(1):55-62
17980713
Circ Res. 1998 Jun 1;82(10):1043-52
9622157
Nat Rev Cancer. 2005 Sep;5(9):699-712
16110318
Mech Dev. 1993 Jan;40(1-2):85-97
8382938
FEBS Lett. 2009 Jan 5;583(1):1-6
19059243
Int J Dev Biol. 2008;52(2-3):229-36
18311713
Development. 1999 May;126(10):2093-102
10207135
EMBO J. 2002 Mar 15;21(6):1398-405
11889045
Oncogene. 2007 May 17;26(23):3423-30
17160023
J Biol Chem. 2006 Oct 20;281(42):31930-9
16920711
Cancer. 2010 Feb 1;116(3):749-57
20029966
Cell. 1995 May 5;81(3):391-401
7736591
Curr Biol. 1999 Jul 29-Aug 12;9(15):837-40
10469569
Genes Dev. 2005 Nov 1;19(21):2631-42
16264195
Development. 2005 Mar;132(6):1327-36
15716344
J Biol Chem. 2007 May 11;282(19):14379-88
17374610
Oncogene. 2008 Jun 12;27(26):3662-72
18212735
APMIS. 2004 Jul-Aug;112(7-8):508-25
15563313
Nat Genet. 1993 Dec;5(4):363-7
8298644
EMBO J. 1995 Oct 2;14(19):4662-75
7588596
Blood. 2006 Jun 1;107(11):4282-90
16467207
FASEB J. 2008 Aug;22(8):2690-701
18424770
FASEB J. 2002 Jul;16(9):1117-9
12039855
Chin Med J (Engl). 2004 Jan;117(1):94-8
14733782
Histopathology. 2005 Jul;47(1):67-73
15982325
Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6273-8
9177207
Development. 1999 May;126(9):1845-57
10101119
Sex Dev. 2007;1(4):238-54
18391535
Curr Opin Genet Dev. 2005 Oct;15(5):542-7
16099645
Nat Genet. 2010 Jan;42(1):89-93
20023660
Arch Biochem Biophys. 2009 Feb;482(1-2):77-82
19046938
Oncogene. 2005 Apr 21;24(18):2992-3001
15735710
Annu Rev Cell Dev Biol. 2006;22:509-29
16822174
Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9618-22
1658787
Trends Cell Biol. 2009 Jan;19(1):8-15
19010680
Blood. 2005 Aug 1;106(3):903-5
15831702
Nature. 1990 Jul 12;346(6280):194-7
2164159
Blood. 2005 Jun 15;105(12):4657-63
15746076