Tanaka T, Tatsuno I, Noguchi Y, Uchida D, Oeda T, Narumiya S, Yasuda T, Higashi H, Kitagawa M, Nakayama K, Saito Y, Hirai A
Second Department of Internal Medicine, Chiba University School of Medicine, Chiba 260,, Japan.
J Biol Chem. 1998 Oct 9;273(41):26772-8. doi: 10.1074/jbc.273.41.26772.
The role of the mevalonate cascade in the control of cell cycle progression in astrocytes has been investigated. Serum stimulation of rat astrocytes in primary culture induces the expression of cyclin E followed by the activation of cyclin-dependent kinase 2 (Cdk2) during G1/S transition. The expression of p27, cyclin D1, and the activities of Cdk4 and Cdk-activating kinase (CAK), composed of Cdk7 and cyclin H, were not affected. Serum did, however, stimulate the expression of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase mRNA at mid-G1 phase. Moreover, an inhibitor of HMG-CoA reductase, pravastatin, reduced cyclin E expression and Cdk2 activation and caused G1 arrest in the astrocytes. In contrast, mevalonate and its metabolite, geranylgeranylpyrophosphate (GGPP) but not farnesylpyrophosphate (FPP), reversed the inhibitory effects of pravastatin on cyclin E expression and Cdk2 activation and allowed G1/S transition. Rho small GTPase(s) were geranylgeranylated and translocated to membranes in the presence of GGPP during G1/S transition. The effect of GGPP on cyclin E expression was abolished by botulinum C3 exoenzyme, which specifically inactivates Rho. These data indicate that geranylgeranylated Rho small GTPase(s) are essential for the induction of cyclin E expression, Cdk2 activation, and G1/S transition in rat astrocytes.
甲羟戊酸级联反应在星形胶质细胞细胞周期进程控制中的作用已得到研究。原代培养的大鼠星形胶质细胞经血清刺激后，在G1/S期转换过程中诱导细胞周期蛋白E的表达，随后激活细胞周期蛋白依赖性激酶2（Cdk2）。p27、细胞周期蛋白D1的表达以及由Cdk7和细胞周期蛋白H组成的Cdk4和Cdk激活激酶（CAK）的活性均未受影响。然而，血清在G1期中期刺激了3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶mRNA的表达。此外，HMG-CoA还原酶抑制剂普伐他汀降低了细胞周期蛋白E的表达和Cdk2的激活，并导致星形胶质细胞G1期停滞。相反，甲羟戊酸及其代谢产物香叶基香叶基焦磷酸（GGPP）而非法尼基焦磷酸（FPP）可逆转普伐他汀对细胞周期蛋白E表达和Cdk2激活的抑制作用，并使G1/S期转换得以进行。在G1/S期转换过程中，Rho小GTP酶在GGPP存在的情况下被香叶基香叶基化并转位至细胞膜。肉毒杆菌C3外切酶可特异性地使Rho失活，从而消除了GGPP对细胞周期蛋白E表达的影响。这些数据表明，香叶基香叶基化的Rho小GTP酶对于大鼠星形胶质细胞中细胞周期蛋白E表达的诱导、Cdk2的激活以及G1/S期转换至关重要。
