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
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.