Identification of connective tissue growth factor as a target of WT1 transcriptional regulation

Abstract

The Wilms tumor suppressor WT1 has transcription-activating and -suppressing capabilities. WT1-responsive promoters have been described; however, in large part, it remains unclear which potential downstream genes are physiologically relevant and mediate the function of WT1 in tumorigenesis and development. To identify genes regulated by WT1 in vivo, we used a dominant-negative version of WT1 to modulate WT1 activity in a Wilms tumor cell line. Screening oligonucleotide arrays with RNA from these cells uncovered a number of genes whose expression was altered by abrogation of WT1 function. Several of the genes encode members of the CCN family of growth regulators. The promoter of one of these genes, connective tissue growth factor (CTGF), is suppressed by WT1 both in its endogenous location and in reporter constructs. WT1 regulation of CTGF expression is not mediated by previously identified WT1 recognition elements and may therefore involve a novel mechanism. Our results indicate that CTGF is a bona fide target of WT1 transcriptional suppression and likely plays a role in Wilms tumorigenesis and associated disease syndromes.