p53 regulates insulin-like growth factor-I (IGF-I) receptor expression and IGF-I-induced tyrosine phosphorylation in an osteosarcoma cell line: interaction between p53 and Sp1.

Abstract

The insulin-like growth factor-I receptor (IGF-IR) is involved in tumorigenesis. The aim of the present study was to investigate whether the IGF-IR is a physiological target for p53 in osteosarcoma cells. The p53-induced regulation of IGF-IR levels was studied in a tetracycline-regulated expression system. When expressed in Saos-2, osteosarcoma cells that lack p53, wild-type p53 decreased, whereas mutated p53 increased IGF-IR expression, and IGF-I-induced tyrosine phosphorylation of the IGF-IR. Similarly, wild-type p53 decreased IGF-I-induced tyrosine phosphorylation of IRS-1. A functional and physical interaction between p53 and Sp1, in the regulation of the IGF-R, was studied in osteosarcoma cells. Expression of p53 decreased IGF-IR promoter activity, whereas no effect on promoter activity was seen by Sp1 expressed alone. However, Sp1 counteracted the inhibitory effect of p53 on IGF-IR promoter activity in a dose-dependent manner. Furthermore, wild-type and mutated p53 were coimmunoprecipitated with Sp1, indicating a physical interaction between p53 and Sp1. In conclusion, p53 regulates IGF-IR expression, as reflected by a reduction in IGF-IR protein and a parallel reduction in IGF-I-induced tyrosine phosphorylation of the IGF-IR and IRS-1 in an osteosarcoma cell line. These data indicate that the IGF-I receptor is a physiological target for p53 in osteosarcoma cells. Furthermore, data supporting an interaction between p53 and Sp1 in the regulation of the promoter activity of IGF-IR are presented.

• Authors: C Ohlsson, N Kley, H Werner, D LeRoith
• Journal: Endocrinology (Endocrinology) Vol. 139 Issue 3 Pg. 1101-7 (Mar 1998) ISSN: 0013-7227 [Print] United States
• PMID: 9492043 (Publication Type: Journal Article)

Chemical References

• Sp1 Transcription Factor
• Tumor Suppressor Protein p53
• Tyrosine
• Insulin-Like Growth Factor I
• Receptor, IGF Type 1

Topics

• Humans
• Insulin-Like Growth Factor I (pharmacology)
• Mutation
• Osteosarcoma (metabolism)
• Phosphorylation
• Promoter Regions, Genetic
• Receptor, IGF Type 1 (analysis, genetics)
• Sp1 Transcription Factor (physiology)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (physiology)
• Tyrosine (metabolism)