| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 1999: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1998: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Phospholipase D (PLD) hydrolyzes phospholipids, especially phosphatidylcholine (PC) to phosphatidic acid (PA) and choline. PA acts as a second messenger and can be converted to other messenger molecules, such as lysophosphatidic acid (LPA) and 1,2-diacylglycerol (DG). Recent cDNA cloning studies have revealed the existence of at least two isozymes (PLD1, PLD2) in mammalian cells. For PLD1, two alternatively spliced forms, PLD1a and PLD1b have been identified. In addition to these, another type of PLD (PLDOA) which is activated by unsaturated fatty acids such as oleic acid has been suggested, although its molecular nature is not known yet. In addition to glycerophospholipids, sphingomyelin hydrolysis is induced by a variety of stress signals including cytokines and chemotheraputic agents. Hydrolysis of sphingomyelin by sphingomyelinase results in the production of ceramide, which is regarded as a second messenger of differentiation and apoptosis. N-acetylsphingosine (CィイD22ィエD2-ceramide
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), a membrane-permeable analogue, inhibits PLD activity in several types of cells, including RBL-2H3 cells, PC12 cells and C6 glioma cells. During apoptotic process of these cells, GTPγS-dependent PLD activity in cell lysates decreased time-dependently. Moreover, mRNA levels of rPLD1a and rPLD1b showed time-dependent decreases. In contrast, the mRNA level of rPLD2 slightly increased. In sharp contrast to the cells listed above, PLD activity was upregulated during apoptosis, induced by actinomycin D, TNF-α or H202, of Jurkat T cells which mainly express PLDOA. The results obtained suggest that even in resting cells PLD produces survival signals. In response to growth or differentiation signals, it is activated and increases the strength of this signal. On the other hand, apoptotic agents trigger death signal transduction as well as shutting off survival signals including GTPγS-dependent PLD activity. By contrast, unregulated activation of PLD, as observed in Jurkat T cells, also causes cell death. Less
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