Increased expression of insulin-like growth factor I receptor in malignant cells expressing aberrant p53: Functional impact
2000 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 60, no 18, 5278-5283 p.Article in journal (Refereed) Published
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 over expressed 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 p21(Waf1) 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.
Place, publisher, year, edition, pages
2000. Vol. 60, no 18, 5278-5283 p.
human-melanoma cells, n-linked glycosylation, mutant p53, wild-type, inhibition, gene, apoptosis, mutation, lines, mechanisms
IdentifiersURN: urn:nbn:se:kth:diva-20056ISI: 000089550600043OAI: oai:DiVA.org:kth-20056DiVA: diva2:338749
QC 201005252010-08-102010-08-10Bibliographically approved