This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ohlsson, C. Articles by LeRoith, D. Search for Related Content PubMed PubMed Citation Articles by Ohlsson, C. Articles by LeRoith, D. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Genetics Home Reference Hazardous Substances DB L-TYROSINE

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

Diabetes Branch (C.O., D.L.), National Institute of Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1770; Department of Molecular Genetics and Cell Biology (N.K.), Oncology Drug Discovery, Bristol-Myers Squid Pharmaceutical Research Institute, Princeton, New Jersey 08540; and Department of Clinical Biochemistry (H.W.), Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel

Address all correspondence and requests for reprints to: Claes Ohlsson, M.D., Ph.D., Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 8S235A, 10 Center Drive, MCS-1770, Bethesda, Maryland 20892-1770. E-mail: claes{at}ss.gu.se

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.