Kit signaling inhibits the sphingomyelin-ceramide pathway through PLCγ1: implication in stem cell factor radioprotective effect

摘要: Previous studies demonstrated that Kit activation confers radioprotection. However, the mechanism by which signaling interferes with cellular response to ionizing radiation (IR) has not been firmly established. Based on role of sphingomyelin (SM) cycle apoptotic pathway in IR-induced apoptosis, we hypothesized one components might inhibit ceramide production or ceramide-induced apoptosis. Results show that, both Ba/F3 and 32D murine cell lines transfected wild-type c-kit, stem factor (SCF) stimulation resulted a significant reduction apoptosis cytotoxicity, whereas DNA repair remained unaffected. Moreover, SCF inhibited neutral sphingomyelinase (N-SMase) production. The inhibitory effect SM was influenced wortmannin, phosphoinositide-3 kinase (PI3K) inhibitor. protective maintained 32D-KitYF719 cells PI3K/Akt is abolished due mutation docking site for PI3K. In contrast, phospholipase C gamma (PLC gamma) inhibition U73122 totally restored N-SMase stimulation, production, Kit-activated cells. did protect 32D-KitYF728 (lacking functional PLC 1), from cycle. Finally, SCF-induced radioprotection human CD34(+) bone marrow also U73122. Altogether, these results suggest 1-dependent negative regulation stimulation. Beyond scope Kit-expressing cells, it suggests 1 status could greatly influence post-DNA damage IR, perhaps, other genotoxic agents.