| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1997: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1996: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Research Abstract |
Protein kinase C (PKC) plays a crucial role a receptor-mediated signal transduction affecting diverse range of cellular responses such as cell proliferation, differentiation, and tumor promotion. PKC is a unique enzyme which is activated by 1,2-diacylglycerol (DAG) produced form receptor-mediated hydrolysis of inositol phosphate. On the othe hand, active oxygen species such as superoxide, hydrogen peroxide, and hydroxy radical have been suggested to play important roles in many pathological events such as inflammation, autoimmune diseases, ischemia-reperfusion injury, atherosclerosis and cardiovascular diseases, and carcinogenesis. This suggests a close relationship between the action of PKC and active oxygen speciesinduced dysfunction and cellular damage, however, this possibility has not been throughly examined. In the present study, we observed that 1-stearoyl-2-linoleoylglycerol hydroperoxide (SLG-OOH) and SLG hydroxide (SLG-OH) stimulated the PKC activity isolated from rat brain m
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ore efficiently than that of unoxidized SLG in the presences of phosphatidylserine and calcium ion. 1,2-dilinoleoylglycerol hydroperoxide (LLG-OOH), LLG-OH,1-palmitoyl-2-linoleoylglycerol hydroperoxide (PLG-OOH), PLG-OH,1-stearoyl-2-arachidonoylglycerol hydroperoxide (SAG-OOH), SAG-OH,1-palmitoyl-2-arachidonoylglycerol hydroperoxide (PAG-OOH), PAG-OH have similar biological effects on rat brain PKC fraction. It is generally accepted that DAG is generated from the hydrolysis of plasma membrane phosphatidylinositol 1,5-bisphosphate by phospholipase C (PLC), or from the hydrolysis of PC by phospholipase D and subsequent conversion of phosphatidic acid to DAG.Recently, however, many reports have disclosed that DAG could be generated directly from the hydrolysis of membrane PC contained in various mammalian cells by PC-specific PLC.Futhermore, it has been reported that PLC has a preference to hydrolyzed oxidized PC.Hence, it is quite conceivable that oxidized DAG (DAG-OOH) is from oxidatively damaged mammalian cell membranes. Then, DAG-OOH may act as a biochemical messenger of oxidative stress to alter the PKC-dependent signal transduction system in manner approaching phorbol 12-myristate acetate. On the other hand, rat brain PKC fraction contains PKC isoforms of alpha, beta, gamma, delta, epusilon, zeta. Interestigly, SLG-OOH specifically activated PKC alpha and delta isoforms, respectively. These results suggested that PKC alpha and delta can be activated through oxidative stress in a manner unrelated receptor-coupled hydrolysis of phosphatidylinositol 1,5-bisphosphate by PLC. Less
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