Matteucci A, Faenza I, Gilmour R S, Manzoli L, Billi A M, Peruzzi D, Bavelloni A, Rhee S G, Cocco L
Consiglio Nazionale delle Ricerche and Cell Biology Laboratory, Istituto Rizzoli, Bologna, Italy.
Cancer Res. 1998 Nov 15;58(22):5057-60.
A body of evidence has shown the existence of a nuclear phosphoinositide cycle in different cell types. The cycle is endowed with kinases as well as phosphatases and phospholipase C (PLC). Among the PLC isozymes, the beta family is characterized by a long COOH-terminal tail that contains a cluster of lysine residues responsible for nuclear localization. Indeed, PLC beta 1 is the major isoform that has been detected in the nucleus of several cells. This isoform is activated by insulin-like growth factor I, and when this isoform is lacking, as a result of gene ablation, the onset of DNA synthesis induced by this hormone is abolished. On the contrary, PLC beta 1 is down-regulated during the erythroid differentiation of Friend erythroleukemia cells. A key question is how PLC beta 1 signaling at the nucleus fits into the erythroid differentiation program of Friend erythroleukemia cells, and whether PLC beta 1 signaling activity is directly responsible for the maintenance of the undifferentiated state of erythroleukemia cells. Here we present evidence that nuclear PLC beta 1 but not the isoform located at the plasma membrane is directly involved in maintaining the undifferentiated state of Friend erythroleukemia cells. Indeed, when wild-type PLC beta 1 is overexpressed in these cells, differentiation in response to DMSO is inhibited in that the expression of beta-globin is almost completely abolished, whereas when a mutant lacking the ability to localize to the nucleus is expressed, the cells differentiate, and the expression of beta-globin is the same as in wild-type cells.
大量证据表明，不同细胞类型中存在核磷酸肌醇循环。该循环中含有激酶、磷酸酶和磷脂酶C（PLC）。在PLC同工酶中，β家族的特点是COOH末端较长，含有负责核定位的赖氨酸残基簇。实际上，PLCβ1是在几种细胞的细胞核中检测到的主要同工型。这种同工型由胰岛素样生长因子I激活，当由于基因缺失而缺乏这种同工型时，该激素诱导的DNA合成起始被消除。相反，在弗氏红白血病细胞的红细胞分化过程中，PLCβ1表达下调。一个关键问题是，细胞核中的PLCβ1信号如何融入弗氏红白血病细胞的红细胞分化程序，以及PLCβ1信号活性是否直接负责维持红白血病细胞的未分化状态。在此，我们提供证据表明，直接参与维持弗氏红白血病细胞未分化状态的是细胞核中的PLCβ1，而非位于质膜的同工型。事实上，当在这些细胞中过表达野生型PLCβ1时，对二甲基亚砜（DMSO）的分化反应受到抑制，因为β珠蛋白的表达几乎完全被消除，而当表达缺乏核定位能力的突变体时，细胞发生分化，β珠蛋白的表达与野生型细胞相同。
