Increased Expression of the Insulin-Like Growth Factor I Receptor Gene, IGF1R, in Wilms Tumor is Correlated with Modulation of IGF1R Promoter Activity by the WT1 Wilms Tumor Gene Product

Wilms tumor is a pediatric neoplasm that arises from the metanephric blastema. The expression of the gene encoding insulin-like growth factor II (IGF-II) is often elevated in these tumors. Since many of the actions of IGF-II are mediated through activation of the IGF-I receptor (IGF-IR), we have mea...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1993-06, Vol.90 (12), p.5828-5832
Main Authors: Werner, Haim, Re, Gian G., Drummond, Iain A., Sukhatme, Vikas P., Rauscher, Frank J., Sens, Donald A., Garvin, A. Julian, LeRoith, Derek, Roberts, Charles T.
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Biological and medical sciences
Cellular biology
CHO cells
Gene Expression
Gene Expression Regulation, Neoplastic
Genes
Genes, Tumor Suppressor
Genetic vectors
Humans
Kidney Neoplasms - genetics
Kidney Neoplasms - metabolism
Kidneys
Medical research
Medical sciences
Messenger RNA
Molecular Sequence Data
Nephrology. Urinary tract diseases
Plasmids
Promoter Regions, Genetic
Rats
Receptor, IGF Type 1 - biosynthesis
Receptor, IGF Type 1 - genetics
Receptors
Regression Analysis
Restriction Mapping
RNA
RNA, Messenger - genetics
RNA, Messenger - metabolism
RNA, Neoplasm - genetics
RNA, Neoplasm - isolation & purification
TATA Box
Tumors
Tumors of the urinary system
Wilms Tumor - genetics
Wilms Tumor - metabolism
Wilms tumors
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Summary:Wilms tumor is a pediatric neoplasm that arises from the metanephric blastema. The expression of the gene encoding insulin-like growth factor II (IGF-II) is often elevated in these tumors. Since many of the actions of IGF-II are mediated through activation of the IGF-I receptor (IGF-IR), we have measured the levels of IGF-IR mRNA in normal kidney and in Wilms tumor samples using solution hybridization/RNase protection assays. IGF-IR mRNA levels in the tumors were 5.8-fold higher than in adjacent normal kidney tissue. Among the tumors themselves, the levels of IGF-IR mRNA in those containing heterologous stromal elements were 2-fold higher (P < 0.01) than in tumors without these elements. IGF-IR gene (designated IGFIR) expression in the tumors was inversely correlated with the expression of the Wilms tumor suppressor gene WT1, whose inactivation appears to be a key step in the etiology of Wilms tumor. Cotransfection of Chinese hamster ovary cells with rat and human IGF-IR gene promoter constructs driving luciferase reporter genes and with WT1 expression vectors showed that the active WT1 gene product represses IGF-IR promoter activity in a dose-dependent manner. These results suggest that underexpression, deletion, or mutation of WT1 may result in increased expression of the IGF-IR, whose activation by IGF-II may be an important aspect of the biology of Wilms tumor.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.90.12.5828