PubMed · 9109799
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M A Birchall. 1997. Fluticasone.. https://doi.org/10.1001/archotol.1997.01900040101017
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Recently we have shown that the majority of retinal ganglion cells (RGCs) dies via activation of caspase-3 after transection of the optic nerve (ON) in the adult rat. In the present study we investigated whether insulin-like growth factor-I (IGF-I), an important factor in retinal development, prevents secondary death of RGCs after axotomy. Moreover, we studied potential intracellular mechanisms of IGF-mediated neuroprotection in more detail. Our results indicate that intraocular application of IGF-I protects RGCs from death after ON transection in a dose-dependent manner. We show reduced caspase-3 activity as one possible neuroprotective mechanism of IGF-I treatment in vivo. Caspase-3 mRNA expression remained unchanged. Because caspase inhibition can be mediated by Akt in vitro, we examined phosphorylation of Akt after axotomy and under IGF treatment. Western blot analysis revealed decreased Akt phosphorylation after axotomy without treatment and an increased phosphorylation of Akt under treatment with IGF-I. This strong increase could be reduced by simultaneous injection of wortmannin (WM), a potent inhibitor of phosphatidylinositol 3-kinase (PI3-K). To prove the pathway suggested by these experiments as relevant for the in vivo situation, we assessed the number of RGCs 14 d after ON transection under a combined treatment strategy of IGF-I and WM. As expected, WM significantly reduced the neuroprotective effects of IGF-I. In summary, we show for the first time in vivo that IGF is neuroprotective via PI3-K-dependent Akt phosphorylation and by inhibition of caspase-3.
In some v-Ha-ras-transfected cell lines, serum deprivation results in apoptosis. Clarification of the molecular mechanisms by which oncogenic Ras controls susceptibility to apoptosis may assist in the development of effective therapies against human cancer with oncogenic ras gene. In this report, we established a v-Ha-ras-transfected human fibroblast clone, R1. In R1 cells, induction of v-Ha-Ras enhanced susceptibility to cell death under serum-deprived conditions. Ladders of cellular DNA were identified only when oncogenic ras was induced under serum-deprived conditions. Platelet-derived growth factor (PDGF) precluded DNA fragmentation of serum-deprived v-Ha-ras-transformed cells. Under serum-depleted conditions, the amounts of activated ERK and Akt decreased as compared with those under serum-containing conditions. The decreased levels of activated ERK and Akt were restored by the addition of PDGF. Inhibition of phosphorylated-ERK and Akt resulted in renewed susceptibility to cell death. These results indicate that failure of signal transduction of oncogenic Ras by the deficiency of growth factors such as PDGF causes v-Ha-Ras-dependent apoptosis.
Phosphatidylinositide-3-OH-kinase (PI 3-kinase) is an upstream activator of p42/p44 mitogen-activated protein kinase (MAPK), but the role of PI 3-kinase-dependent MAPK remains obscure. Here we demonstrate that in a variety of different cell types, PI 3-kinase inhibition results in an inhibition of MAPK in unstimulated cells but does not interfere with growth factor-, or TPA-induced MAPK activity. Furthermore, inhibition of either PI 3-kinase or MEK/MAPK results in cell death in serum-starved cells. We concluded that basal, but not induced MAPK activity is mediated by PI 3-kinase and that this PI 3-kinase-mediated MEK/MAPK activity is essential for cell survival in quiescent cells.