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

Girnita, L. (författare)
Karolinska Institutet
Girnita, A. (författare)
Karolinska Institutet
Brodin, B. (författare)
Karolinska Institutet
visa fler...
Xie, Y. T. (författare)
Nilsson, G. (författare)
Karolinska Institutet
Dricu, A. (författare)
Lundeberg, Joakim (författare)
KTH,Bioteknologi
Wejde, J. (författare)
Karolinska Institutet
Bartolazzi, A. (författare)
Karolinska Institutet
Wiman, K. G. (författare)
Karolinska Institutet
Larsson, O. (författare)
Karolinska Institutet
visa färre...
 (creator_code:org_t)
2000
2000
Engelska.
Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 60:18, s. 5278-5283
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • 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.

Nyckelord

human-melanoma cells
n-linked glycosylation
mutant p53
wild-type
inhibition
gene
apoptosis
mutation
lines
mechanisms

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art (ämneskategori)

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