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五十多年前,瓦勃(warburg)发现恶性肿瘤此绝大多数正常细胞能更迅速地将葡萄糖酵解成乳酸。分析各种肿瘤的这一现象时,我们发现一个共同的特征:即ATP分解释放糖酵解所需要之ADP和Pi的速度很快。但ATP酶的来源不同,有的细胞是Na~+、K~+-依赖ATP酶;有些是线粒体ATP酶;还有一些则可能是病毒ATP酶。艾氏腹水瘤细胞的质膜Na~+、K~+-泵不起作用。从细胞中泵出一个钠离子,要分解几分子ATP,从而生成对酵解起限速作用的ADP和Pi,使乳酸迅速形成。Na~+、K~+-泵由两个亚基组成:α-亚基含ATP酶的活性中心,而β-亚基是一个功能不明的糖蛋白。在肿瘤细胞质膜中有一种蛋白激酶(PK_M),它催化β-亚基磷酸化,从而使Na~+、K~+-泵失效。这种蛋白激酶又依次受另外三个蛋白激酶(PKs、PK_L和PK_F)逐级激活,PK_F与Rous肉瘤病毒的Src基因产物在免疫上相似。每种蛋白激酶逐级磷酸化另一个蛋白质底物,包括细胞骨架成分在内。这些可以有助于解释在转化过程中基因多效性表现(pleiotropic manifestations)是由单一基因调控的。
More than fifty years ago, Warburg found that the vast majority of normal cells in this malignancy glycolysis lactic acid more rapidly. When we analyzed this phenomenon in various tumors, we found a common feature: that ATP decomposes the ADP and Pi that are needed to release glycolysis quickly. However, the sources of ATPase are different, some cells are Na~+, K~+-dependent ATPases, some are mitochondrial ATPases, and some are probably viral ATPases. The plasma membrane Na~+, K~+- pumps of Ehrlich ascites tumor cells do not work. A sodium ion is pumped out of the cell to decompose a few molecules of ATP to produce ADP and Pi, which act on the rate of fermentation, causing rapid formation of lactic acid. The Na~+, K~+- pump consists of two subunits: the alpha-subunit contains the active center of the ATPase, and the beta-subunit is an unclear glycoprotein. There is a protein kinase (PK_M) in the plasma membrane of tumor cells, which catalyzes the phosphorylation of the β-subunit, thereby rendering the Na~+, K~+- pumps ineffective. This protein kinase in turn is sequentially activated by three additional protein kinases (PKs, PK_L, and PK_F) that are immunologically similar to Rous sarcoma virus Src gene products. Each protein kinase phosphorylates another protein substrate step by step, including the cytoskeletal component. These can help explain that pleiotropic manifestations are regulated by a single gene during transformation.