Gabuzda D, Busciglio J, Yankner B A
Department of Neurology, Harvard Medical School, Boston, Massachusetts.
J Neurochem. 1993 Dec;61(6):2326-9. doi: 10.1111/j.1471-4159.1993.tb07479.x.
The cellular factors regulating the generation of beta-amyloid from the amyloid precursor protein (APP) are unknown. Activation of protein kinase C (PKC) by phorbol ester treatment inhibited the generation of the 4-kDa beta-amyloid peptide in transfected COS cells, a human glioma cell line, and human cortical astrocytes. An analogue of diacylglycerol, the endogenous cellular activator of PKC, also inhibited the generation of beta-amyloid. Activation of PKC increased the level of secreted APP in transfected COS cells but did not significantly affect the level of secreted APP in primary human astrocytes or in the glioma cell line. Cell-associated APP and the secreted APP derivative, but not beta-amyloid, were phosphorylated on serine residues. Activation of PKC did not increase the level of APP phosphorylation, suggesting that PKC modulates the proteolytic cleavage of APP indirectly by phosphorylation of other substrates. These results indicate that PKC activation inhibits beta-amyloid production by altering APP processing and suggest that beta-amyloid production can be regulated by the phospholipase C-diacylglycerol signal transduction pathway.
调节淀粉样前体蛋白（APP）生成β-淀粉样蛋白的细胞因子尚不清楚。佛波酯处理激活蛋白激酶C（PKC）可抑制转染的COS细胞（一种人胶质瘤细胞系）以及人皮质星形胶质细胞中4 kDaβ-淀粉样肽的生成。二酰基甘油（PKC的内源性细胞激活剂）的类似物也可抑制β-淀粉样蛋白的生成。PKC的激活增加了转染的COS细胞中分泌型APP的水平，但对原代人星形胶质细胞或胶质瘤细胞系中分泌型APP的水平没有显著影响。细胞相关的APP和分泌型APP衍生物在丝氨酸残基上发生磷酸化，但β-淀粉样蛋白未发生磷酸化。PKC的激活并未增加APP的磷酸化水平，这表明PKC通过对其他底物的磷酸化间接调节APP的蛋白水解切割。这些结果表明，PKC激活通过改变APP加工过程来抑制β-淀粉样蛋白的产生，并提示β-淀粉样蛋白的产生可受磷脂酶C-二酰基甘油信号转导途径的调节。
