Increased expression of insulin-like growth factor I receptor in malignant cells 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 cell line, a transfectant carrying temperature-sensitive (ts) p53 and endogenous mutant p53 (codon 248), we demonstrated a drastic down-regulation of plasma membrane-bound IGF-IRs on induction of wild-type p53. However, a similar response was obtained by treatment of BL-41tsp53-2 cells expressing mutant 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 overexpressed p53 were investigated. The BE cell line has a "hot spot" mutation (codon 248) and expresses only codon 248-mutant p53. SK-MEL-28 has a point mutation at codon 145. SK-MEL-5 cells did not exhibit any p53 mutations, but the absence of p21Waf1 expression suggested functionally aberrant p53. Our data suggest that interaction with Mdm-2 may underlie p53 inactivation in these cells. Using p53 antisense oligonucleotides, we demonstrated a substantial down-regulation of cell surface expression of IGF-IR proteins in all melanoma cell lines after 24 h. This was paralleled by decreased tyrosine phosphorylation of IGF-IR and growth arrest, and, subsequently, massive cell death was observed (this was also seen in BL-41tsp53-2 cells with mutant conformation of ts p53). Taken together, our results suggest that up-regulation of IGF-IR as a result of expression of aberrant p53 may be important for the growth and survival of malignant cells.
Girnita
L
L
Department of Oncology/Pathology, Karolinska Hospital, Stockholm, Sweden.
Girnita
A
A
Brodin
B
B
Xie
Y
Y
Nilsson
G
G
Dricu
A
A
Lundeberg
J
J
Wejde
J
J
Bartolazzi
A
A
Wiman
K G
KG
Larsson
O
O
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D015853:Cysteine Proteinase Inhibitors; D016376:Oligonucleotides, Antisense; D016159:Tumor Suppressor Protein p53; C067713:lactacystin; D017526:Receptor, IGF Type 1; D000111:Acetylcysteine