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

The insulin-like growth factor-I receptor (IGF-IR) is involved in tumo rigenesis. The aim of the present study was to investigate whether the IGF-IR is a physiological target for p53 in osteosarcoma cells. The p 53-induced regulation of IGF-IR levels was studied in a tetracycline-r egulated expression system. When expressed in Saos-2, osteosarcoma cel ls that lack p53, wild-type p53 decreased, whereas mutated p53 increas ed IGF-IR expression, and IGF-I-induced tyrosine phosphorylation of th e IGF-IR. Similarly, wild-type p53 decreased IGF-I-induced tyrosine ph osphorylation of IRS-1. A functional and physical interaction between p53 and Spl, in the regulation of the IGF-R, was studied in osteosarco ma cells. Expression of p53 decreased IGF-IR promoter activity, wherea s no effect on promoter activity was seen by Spl expressed alone. Howe ver, Spl counteracted the inhibitory effect of p53 on IGF-IR promoter activity in a dose-dependent manner. Furthermore, wild-type and mutate d p53 were coimmunoprecipitated with Spl, indicating a physical intera ction between p53 and Spl. In conclusion, p53 regulates IGF-IR express ion, as reflected by a reduction in IGF-IR protein and a parallel redu ction 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 rec eptor is a physiological target for p53 in osteosarcoma cells. Further more, data supporting an interaction between p53 and Spl in the regula tion of the promoter activity of IGF-IR are presented.