Epidermal growth factor protects fibroblasts from apoptosis via PI3 kinase and Rac signaling pathways.
The fibroplasia noted during wound repair is resolved by fibroblast cell death. How fibroblasts undergo death and how this is prevented by trophic growth factors present during the regenerative phase are unknown at the molecular level. We examined a model of staurosporine-induced apoptosis in fibroblasts. We demonstrated that epidermal growth factor (EGF) stimulation of fibroblast NR6WT expressing human EGF receptors blocks staurosporine-induced apoptosis by inhibiting the activation of caspase-3. The survival effect of EGF on rescuing apoptotic NR6WT involves signaling pathways that derive from PI3K and Rac; the blockade of apoptosis is abolished when PI3K and Rac signals are inhibited simultaneously. Furthermore, by using KP372-1, a specific Akt inhibitor, we found that downstream of Akt signaling pathways is absolutely required for the EGF rescue from staurosporine-induced apoptosis in NR6WT. Interestingly, EGF prevention of apoptosis induced by tumor necrosis factor-alpha in the face of cycloheximide blockade of protein translation occurs via a different set of pathways as the simultaneous inhibition of extracellular signal-regulated kinase, Rac, and PI3K signaling did not eliminate EGF from rescuing fibroblasts in the face of this cytokine. These findings indicate that EGF receptor activation provides survival response against staurosporine-induced apoptosis through signal pathways of PI3K and Rac, which then may prevent the activation of caspase-3.
Shao
Hanshuang
H
Department of Pathology, University of Pittsburgh, and Department of Pathology, Pittsburgh VAMC, Pittsburgh, Pennsylvania 15261, USA.
Yi
Xiao-Ming
XM
Wells
Alan
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D010957:Plasmids; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D019311:Staurosporine