Nucleic Acids Research, Vol 24, Issue 6 1149-1157, Copyright © 1996 by Oxford University Press
JA Moshier, M Skunca, W Wu, SM Boppana, FJ Rauscher 3rd and J Dosescu
The importance of ornithine decarboxylase (ODC) to cell proliferation is
underscored by the complex array of cell-specific mechanisms invoked to
regulate its synthesis and activity. Misregulation of ODC has severe
negative consequences on normal cell function, including the acquisition of
tumorigenic growth properties by cells overexpressing ODC. We hypothesize
that ODC gene expression is a candidate target for the anti-proliferative
function of certain tumor suppressors. Here we show that the Wilms' tumor
suppressor WT1 binds to multiple sites within the human ODC promoter, as
determined by DNase I protection and methylation interference assays. The
expression of WT1 in transfected HCT 116, NIH/3T3 and HepG2 cells represses
activity of the ODC promoter controlling expression of a luciferase
reporter gene. In contrast WT1 expression enhances ODC promoter activity in
SV40-transfected HepG2 cells. Both the extent of modulation of ODC gene
expression and the mediating WT1 binding elements are cell specific.
Constructs expressing WT1 deletion mutants implicate two regions required
for repressor function, as well as an intrinsic activation domain.
Understanding the regulation of ODC gene expression by WT1 may provide
valuable insights into the roles of both WT1 and ODC in development and
tumorigenesis.
ARTICLES
Regulation of ornithine decarboxylase gene expression by the Wilms' tumor suppressor WT1
Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI 48201 USA.
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