Identification of connective tissue growth factor as a target of WT1 transcriptional regulation.
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.
Stanhope-Baker
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P
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Williams
B R
BR
D000951:Antigens, Neoplasm; D001483:Base Sequence; D055513:Connective Tissue Growth Factor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D016162:Genes, Wilms Tumor; D006133:Growth Substances / Q000235:genetics*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins; D007680:Kidney Neoplasms; D007700:Kinetics; D008934:Mitogens / Q000235:genetics; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D025721:WT1 Proteins; D009396:Wilms Tumor; D016335:Zinc Fingers
D000951:Antigens, Neoplasm; C526317:CCN2 protein, human; D004268:DNA-Binding Proteins; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; C072013:MAGEA3 protein, human; D008934:Mitogens; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D025721:WT1 Proteins; D055513:Connective Tissue Growth Factor