Role of tyrosine phosphorylation of phospholipase C gamma 1 in the signaling pathway of HMG-CoA reductase inhibitor-induced cell death of L6 myoblasts

Our previous studies have shown that the HMG-CoA reductase (HCR) inhibitor (HCRI), simvastatin, kills L6 myoblasts by involving Ca2+ mobilization from the Ca2+ pool in the cells but not by influx from extracellular space, Mor e recently, we found that HCRI induced tyrosine phosphorylation of several cellular proteins, followed by apoptotic cell death of L6 myoblasts, The pr esent study was aimed to elucidate the molecular target(s) of these tyrosin e phosphorylations induced by HCRI and demonstrated that sinvastatin induce s tyrosine phosphorylation of phospholipase C (PLC) gamma 1, This tyrosine phosphorylation of PLC-gamma 1 caused the increment of the intracellular in ositol triphosphate (IP3) levels in L6 myoblasts, Pretreatment of the cells with herbimycin A, a specific inhibitor of protein tyrosine kinase, inhibi ted a simvastatin-induced increase in IP3 level in the cells as well as tyr osine phosphorylation of PLC-gamma 1. Interestingly, pretreatment of the ce lls with U-73122, a specific inhibitor of PLC, prevented simvastatin-induce d cell death. Thus, these results strongly suggest that simvastatin-induced tyrosine phosphorylation of PLC-gamma 1 plays, at least in part, an import ant role for the development of simvastatin-induced cell death, (C) 1999 Fe deration of European Biochemical Societies.