The Wilms' tumor gene product represses the transcription of thrombospondin 1 in response to overexpression of c-Jun

Citation
V. Dejong et al., The Wilms' tumor gene product represses the transcription of thrombospondin 1 in response to overexpression of c-Jun, ONCOGENE, 18(20), 1999, pp. 3143-3151
Citations number
52
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
ONCOGENE
ISSN journal
09509232 → ACNP
Volume
18
Issue
20
Year of publication
1999
Pages
3143 - 3151
Database
ISI
SICI code
0950-9232(19990520)18:20<3143:TWTGPR>2.0.ZU;2-8
Abstract
Thrombospondin 1 (TSP1) is known for its significant anti-angiogenic proper ties. In a previous study, we have shown that transient or stable overexpre ssion of the transcription factor c-Jun, in rat fibroblasts, leads to repre ssion of TSP1, We now demonstrate that the c-Jun-induced repression of TSP1 does not occur directly and does not require binding of c-Jun to the TSP1 promoter. Instead, repression involves a factor secreted by c-Jun-overexpre ssing cells. This secreted factor triggers a signal transduction pathway fr om the membrane to the nucleus, and these signals lead to the binding of th e product of the Wilms' tumor suppressor gene, WT1, to the -210 region of t he TSP1 promoter, This region binds WT1 and SP1, but not EGR1, although its sequence fits the consensus binding site for this transcription factor. WT 1 overexpression in transfected cells inhibits endogenous TSP1 gene express ion and TSP1 transcription in experiments using TSP1 promoter-reporter cons tructs. The WT1-KTS isoform is more active in repressing TSP1 transcription than WT1+KTS, while EGR1 is inactive, Enhancement of WT1 binding to DNA in response to c-Jun does not require de novo protein synthesis. The above me chanism for TSP1 repression could apply to other genes, thus coordinating t heir regulation in the vicinity of a c-Jun-overexpressing cell. We conclude that WT1, which was discovered as a result of its tumor suppressor propert ies, may also possess oncogenic characteristics in the c-Jun transformation process, and thus repress the antiangiogenic protein, TSP1.