TY - JOUR
T1 - Role of tyrosine phosphorylation of phospholipase C γ1 in the signaling pathway of HMG-CoA reductase inhibitor-induced cell death of L6 myoblasts
AU - Mutoh, Tatsuro
AU - Kumano, Takanori
AU - Nakagawa, Hiroto
AU - Kuriyama, Masaru
N1 - Funding Information:
We thank Sankyo Pharmaceutical Co. Ltd. for the generous gift of HCRIs, simvastatin and pravastatin. This work was supported in part by a grant-in-aid from the Ministry of Education, Science, Sports and Culture of Japan to T.M.
PY - 1999/3/5
Y1 - 1999/3/5
N2 - 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. More recently, we found that HCRI induced tyrosine phosphorylation of several cellular proteins, followed by apoptotic cell death of L6 myoblasts. The present study was aimed to elucidate the molecular target(s) of these tyrosine phosphorylations induced by HCRI and demonstrated that simvastatin induces tyrosine phosphorylation of phospholipase C (PLC) γ1. This tyrosine phosphorylation of PLC-γ1 caused the increment of the intracellular inositol triphosphate (IP3) levels in L6 myoblasts. Pretreatment of the cells with herbimycin A, a specific inhibitor of protein tyrosine kinase, inhibited a simvastatin-induced increase in IP3 level in the cells as well as tyrosine phosphorylation of PLC-γ1. Interestingly, pretreatment of the cells with U-73122, a specific inhibitor of PLC, prevented simvastatin-induced cell death. Thus, these results strongly suggest that simvastatin-induced tyrosine phosphorylation of PLC-γ1 plays, at least in part, an important role for the development of simvastatin-induced cell death. Copyright (C) 1999 Federation of European Biochemical Societies.
AB - 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. More recently, we found that HCRI induced tyrosine phosphorylation of several cellular proteins, followed by apoptotic cell death of L6 myoblasts. The present study was aimed to elucidate the molecular target(s) of these tyrosine phosphorylations induced by HCRI and demonstrated that simvastatin induces tyrosine phosphorylation of phospholipase C (PLC) γ1. This tyrosine phosphorylation of PLC-γ1 caused the increment of the intracellular inositol triphosphate (IP3) levels in L6 myoblasts. Pretreatment of the cells with herbimycin A, a specific inhibitor of protein tyrosine kinase, inhibited a simvastatin-induced increase in IP3 level in the cells as well as tyrosine phosphorylation of PLC-γ1. Interestingly, pretreatment of the cells with U-73122, a specific inhibitor of PLC, prevented simvastatin-induced cell death. Thus, these results strongly suggest that simvastatin-induced tyrosine phosphorylation of PLC-γ1 plays, at least in part, an important role for the development of simvastatin-induced cell death. Copyright (C) 1999 Federation of European Biochemical Societies.
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U2 - 10.1016/S0014-5793(99)00188-X
DO - 10.1016/S0014-5793(99)00188-X
M3 - Article
C2 - 10100621
AN - SCOPUS:0033053865
VL - 446
SP - 91
EP - 94
JO - FEBS Letters
JF - FEBS Letters
SN - 0014-5793
IS - 1
ER -