WT1-p53 interactions in insulin-like growth factor-I receptor gene regulation.

Abstract

The insulin-like growth factor-I receptor (IGF-IR) plays a critical role in transformation. The expression of the IGF-IR gene is negatively regulated by a number of transcription factors, including the WT1 and p53 tumor suppressors. Previous studies have suggested both physical and functional interactions between the WT1 and p53 proteins. The potential functional interactions between WT1 and p53 in control of IGF-IR promoter activity were addressed by transient coexpression of vectors encoding different isoforms of WT1, together with IGF-IR promoter-luciferase reporter constructs, in p53-null osteosarcoma-derived Saos-2 cells, wild-type p53-expressing kidney tumor-derived G401 cells, and mutant p53-expressing, rhabdomyosarcoma-derived RD cells. Similar studies were also performed to compare p53-expressing Balb/c-3T3 and clonally derived p53-null, (10)1 fibroblasts and the colorectal cancer cell line HCT116 +/+, which expresses a wild-type p53 gene, and its HCT116 -/- derivative, in which the p53 gene has been disrupted by homologous recombination. WT1 splice variants lacking a KTS insert between zinc fingers 3 and 4 suppressed IGF-IR promoter activity in the absence of p53 or in the presence of wild-type p53. WT1 variants that contain the KTS insert are impaired in their ability to bind to the IGF-IR promoter and are unable to suppress IGF-IR promoter. In the presence of mutant p53, WT1 cannot repress the IGF-IR promoter. Coimmunoprecipitation experiments showed that p53 and WT1 physically interact, whereas electrophoretic mobility shift assay studies revealed that p53 modulates the ability of WT1 to bind to the IGF-IR promoter. In summary, the transcriptional activity of WT1 proteins and their ability to function as tumor suppressors or oncogenes depends on the cellular status of p53.

• Authors: Gila Idelman, Tova Glaser, Charles T Roberts Jr, Haim Werner
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 5 Pg. 3474-82 (Jan 31 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12444079 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Protein Isoforms
• Recombinant Proteins
• Tumor Suppressor Protein p53
• WT1 Proteins
• Receptor, IGF Type 1

Topics

• Bone Neoplasms
• Cell Cycle (physiology)
• Gene Deletion
• Gene Expression Regulation (physiology)
• Genetic Vectors
• Humans
• Osteosarcoma
• Promoter Regions, Genetic
• Protein Biosynthesis
• Protein Isoforms (genetics, metabolism)
• Receptor, IGF Type 1 (genetics)
• Recombinant Proteins (metabolism)
• Transcription, Genetic
• Transfection
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (genetics, metabolism)
• WT1 Proteins (genetics, metabolism)