Cocco L, Capitani S, Maraldi N M, Mazzotti G, Barnabei O, Gilmour R S, Manzoli F A
Institute of Human Anatomy, University of Bologna, Italy.
Adv Enzyme Regul. 1996;36:101-14. doi: 10.1016/0065-2571(95)00007-0.
The involvement of phospholipids and in particular polyphosphoinositides in cellular signalling has been documented in detail in the last 20 years. In addition to the plasma membrane localization also the nucleus is shown to be a site for both synthesis and hydrolysis of the phosphorylated forms of phosphatidylinositol. Previous observation have established that the nucleus possesses a specific PLC for inositol lipids, i.e., the PLC beta 1 isoform, which undergoes rapid and transient activation after IGF-I stimulation of quiescent Swiss 3T3 cells and is down-regulated after treatment of Friend erythroleukemia cells with DMSO. Here we have reviewed: (i) the potential of nuclear PLC beta 1 to be a target for anti-cancer drug, (ii) the capability of this PLC isoform, when activated by IGF-I, to be a key signalling molecule in the onset of DNA synthesis, via DAG generation and PKC alpha translocation to the nucleus, (iii) the chromosome mapping of PLC beta 1 gene. The differentiation program of Friend cells can be activated by other agents besides DMSO including tiazofurin, an anti-tumor drug, also capable of affecting the nuclear inositol lipid cycle. Tiazofurin induces a lowering of the activity of PLC beta 1 due to down regulation of this isoform as revealed by both Western blotting and Northern blotting analyses. Using Swiss 3T3 cells stably transformed with an antisense PLC beta 1 construct, the knock-out of the PLC beta 1 gene induces both a loss of PLC beta 1 expression, as determined by Western blots, and a loss of the mitogenic responsiveness to IGF-I. These events show a direct relationship between nuclear PLC beta 1 evoked signals and IGF-I induced cell proliferation. Finally, the assignment of the PLC beta 1 gene to the band q35-36 of rat chromosome 3 paves the way for further genetic studies given the fact that the region where PLC beta 1 gene maps is a hot spot for genetic alterations in a number of experimentally induced rat tumors. Taken as a whole, these results assign a key role to the regulation of nuclear PLC activity and expression both in growth-factor activated mitogenesis and in in vitro erythroid differentiation.
在过去20年中，磷脂尤其是多磷酸肌醇参与细胞信号传导的过程已得到详细记录。除了质膜定位外，细胞核也被证明是磷脂酰肌醇磷酸化形式合成和水解的场所。先前的观察已经证实，细胞核拥有一种特异性的肌醇脂质磷脂酶C，即磷脂酶Cβ1亚型，在静止的瑞士3T3细胞受到IGF-I刺激后，它会迅速短暂激活，而在用二甲基亚砜处理弗氏红白血病细胞后会下调。在此我们综述了：(i) 细胞核磷脂酶Cβ1作为抗癌药物靶点的潜力；(ii) 这种磷脂酶C亚型在被IGF-I激活后，通过生成二酰甘油和蛋白激酶Cα转位至细胞核，成为DNA合成起始过程中关键信号分子的能力；(iii) 磷脂酶Cβ1基因的染色体定位。除二甲基亚砜外，弗氏细胞的分化程序还可被其他试剂激活，包括噻唑呋林，一种抗肿瘤药物，它也能够影响细胞核肌醇脂质循环。如蛋白质印迹法和Northern印迹法分析所示，噻唑呋林通过下调该亚型导致磷脂酶Cβ1活性降低。使用稳定转染反义磷脂酶Cβ1构建体的瑞士3T3细胞，磷脂酶Cβ1基因的敲除导致蛋白质印迹法测定的磷脂酶Cβ1表达缺失，以及对IGF-I的促有丝分裂反应性丧失。这些事件表明细胞核磷脂酶Cβ1引发的信号与IGF-I诱导的细胞增殖之间存在直接关系。最后，将磷脂酶Cβ1基因定位于大鼠3号染色体的q35-36带，鉴于磷脂酶Cβ1基因所在区域是多种实验诱导的大鼠肿瘤中基因改变的热点，这为进一步的遗传学研究铺平了道路。总体而言，这些结果表明细胞核磷脂酶C活性和表达的调节在生长因子激活的有丝分裂以及体外红系分化中均起着关键作用。
