Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts.

Abstract

Fibroblast cell lines, designated R-and W cells, were generated, respectively, from mouse embryos homozygous for a targeted disruption of the Igflr gene, encoding the type 1 insulin-like growth factor receptor, and from their wild-type littermates. W cells grow normally in serum-free medium supplemented with various combinations of purified growth factors, while pre-and postcrisis R-cells cannot grow, as they are arrested before entering the S phase. R-cells are able to grow in 10% serum, albeit more slowly than W cells, and with all phases of the cell cycle being elongated. An activated Ha-ras expressed from a stably transfected plasmid is unable to overcome the inability of R-cells to grow in serum-free medium supplemented with purified growth factors but stimulates their growth in 10% serum and also induces the formation of small foci in some clones. Nevertheless, even in the presence of serum, R-cells stably transfected with Ha-ras, alone or in combination with simian virus 40 large T antigen, fail to form colonies in soft agar. Reintroduction into Rcells (or their derivatives) of a plasmid expressing the human insulin-like growth factor I receptor RNA and protein restores their ability to grow with purified growth factors or in soft agar. The signaling pathways participating in cell growth and transformation are discussed on the basis of these results.

Regulation of survivin expression by IGF-1/mTOR signaling

“…One such pathway is centered on IGF-1 ligation to its cognate membrane receptor, which has been shown to increase survivin expression in prostate (Zhang et al, 2005), myeloma (Stromberg et al, 2006) and liver (Hopfner et al, 2006) tumor cell types, even though the underlying mechanism(s) of this response had remained elusive. As now reported here, this pathway depends on IGF-IR transforming potential (Sell et al, 1994), does not involve changes in cell cycle distribution and is not associated with de novo survivin promoter activity or increased survivin protein stability. Conversely, IGF-1 modulates survivin levels by favoring stabilization and translation of a survivin mRNA pool through activation of the mTOR pathway.…”

“…When incubation reactions were prolonged to 48 h, IGF-1 and rapamycin were replaced daily in fresh medium. MEF from IGF-IR null mice (RÀ), or MEF transfected with human WT IGF-IR were cultured as described (Sell et al, 1994). RÀ cells were transduced with retroviral particles expressing IGF-IR mutants GR35 and GR48, and stable cell lines were selected using geneticin (1 mg/ ml).…”

Overexpression of insulin-like growth factor-1 induces hyperplasia, dermal abnormalities, and spontaneous tumor formation in transgenic mice

“…Evidence for the involvement of IGF-1 signaling in tumorigenesis comes from several distinct observations as follows: (i) tumors originating from breast (Yee et al, 1989), colon (Tricoli et al, 1986), and lung (Minuto et al, 1986) in humans, and skin in mouse (Rho et al, 1996) have been shown to overexpress either IGF-1, IGF-1r or both; (ii) overexpression of IGF-1r confers ligand dependent transformation in cultured cells (Kaleko et al, 1990); (iii) IGF-1 expression is elevated in cells carrying an activated p21 Ha-ras (Dawson et al, 1995); (iv) IGF-1 has been shown to induce the expression of other mitogenic growth factors (Vardy et al, 1995); and (v) ®broblasts obtained from IGF-1r null mice were highly resistant to transformation by SV40-T antigen, activated Ha-ras, or a combination of both, while re-introduction of wild-type IGF-1r again conferred susceptibility to transformation (Sell et al, 1993 andSell et al, 1994).…”

A recombinant humanized anti‐insulin‐like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti‐epidermal growth factor receptor therapy against human cancer xenografts

“…The crucial finding that clearly pointed out the major role played by the IGF-IR in cellular transformation was the demonstration that knock-out mouse embryo cells for this receptor are refractory to transformation by viruses, oncogenes and by other overexpressed growth factors receptors; each of these conditions that readily transform cells. 20,21 Relevant to the role of IGF-IR in tumorigenesis is its anti-apoptotic function, IGF-IR has been shown to protect tumor cells from apoptosis in vivo. 22 Overexpression of IGF-IR protects cells from UV irradiation-, cytokine-and gamma radiation-induced apoptosis.…”