Increased expression of insulin-like growth factor I receptor in malignantcells expressing aberrant p53: Functional impact

We investigated the functional impact of p53 on insulin-like growth factor I receptor (IGF-IR) expression in malignant cells. Using the BL-41tsp53-2 c ell line, a transfectant carrying temperature-sensitive (ts) p53 and endoge nous mutant p53 (codon 248), we demonstrated a drastic down-regulation of p lasma membrane-bound IGF-IRs on induction of wild-type p53, However, a simi lar response was obtained by treatment of BL-41tsp53-2 cells expressing mut ant ts p53 with a p53 antisense oligonucleotide. Thus, even if the negative effect of wild-type p53 predominates under a competitive condition, these data indicate that mutant p53 may be important for up-regulation of IGF-IR, To further elucidate this issue, three melanoma cell lines (BE, SK-MEL-5, and SK-MEL-28) that over expressed p53 were investigated. The BE cell line has a "hot spot" mutation (codon 248) and expresses only codon 248-mutant p 53, SK-MEL-28 has a point mutation at codon 145. SK-MEL-5 cells did not exh ibit any p53 mutations, but the absence of p21(Waf1) expression suggested f unctionally aberrant p53. Our data suggest that interaction with Mdm-2 may underlie p53 inactivation in these cells, Using p53 antisense oligonucleoti des, we demonstrated a substantial down-regulation of cell surface expressi on of IGF-IR proteins in all melanoma cell lines after 24 h, This was paral leled by decreased tyrosine phosphorylation of IGF-IR and growth arrest, an d, subsequently, massive cell death was observed (this was also seen in BL- 41tsp53-2 cells with mutant conformation of ts p53). Taken together, our re sults suggest that up-regulation of IGF-IR as a result of expression of abe rrant p53 may be important for the growth and survival of malignant cells.