IGF-I receptor signaling in mammalian cell growth and transformation
Abstract
R$-$ and W cells were generated from mouse embryos homozygous for a null mutation of the IGF-1R genes or from wildtype littermates, respectively. R$-$ cells have several growth defects compared to W cells. The role of IGF-1R signaling in cell growth and transformation was studied using the R$-$ and W cell system. The roles of H-ras, p42mapk, and p90rsk were examined by either stable overexpression in R$-$ and W cells and assaying for parameters of growth or by in vitro kinase assays following stimulation of W, R$-$ R+ (R$-$ cells overexpressing the wildtype IGF-1R) and R$-$/Y950f (R$-$ cells overexpressing a mutant IGF-1R) cells with various growth factors. Activated H-ras but not wildtype H-ras was able to induce DNA synthesis in quiescent R$-$ cells following stimulation with PDGF, EGF, and IGF-1 however, neither was able to induce proliferation of R$-$ cells grown in serum-free medium supplemented with PDGF, EGF, and IGF-1. Activated H-ras, but not wildtype H-ras, was able to induce foci formation in R$-$ cells, however neither was able to induce growth in soft agar. Transient and prolonged p42mapk and p90rsk activation was induced by IGF-1 in W and R+ cells but not in R$-$ and R$-$/Y950F cells. Addition of PDGF and EGF enhanced IGF-1 transient p42mapk and p90rsk activation levels, however, had no effect on prolonged activation levels. PDGF and PDGF and EGF induced transient, but not prolonged p42mapk activity in W, R$-$, R+, and R$-$/Y950F cells. EGF and insulin (separately) induced only transient p42mapk activation in R$-$ and R$-$/Y950 cells while transient and prolonged activation was observed in W and R+ cells. p42mapk activation in TC4 and R$-$/Y1251 cells (R$-$ cells containing C-terminus mutant IGF-1Rs) in response to PDGF, EGF, and IGF-1 and IGF-1 alone resembled that observed in W and R+ cells. Maximal transient and prolonged p42mapk and p90rsk activation was found to correlate with proliferation. Thus, the IGF-1R is necessary for the generation of responses required for proliferation of cells grown in serum-free medium supplemented with PDGF, EGF, and IGF-1 and is also necessary for transformation.
Subject Area
Molecular biology|Cellular biology
Recommended Citation
Swantek, Jennifer Lynn, "IGF-I receptor signaling in mammalian cell growth and transformation" (1996). ProQuest ETD Collection - Thomas Jefferson University. AAI9633532.
https://jdc.jefferson.edu/dissertations/AAI9633532
