Hirai A, Nakamura S, Noguchi Y, Yasuda T, Kitagawa M, Tatsuno I, Oeda T, Tahara K, Terano T, Narumiya S, Kohn L D, Saito Y
Second Department of Internal Medicine, Chiba University Medical School, Inohana-cho, Chuou-ku, Japan.
J Biol Chem. 1997 Jan 3;272(1):13-6.
Cyclin-dependent kinase (Cdk) enzymes are activated for entry into the S phase of the cell cycle. Elimination of Cdk inhibitor protein p27Kip1 during the G1 to S phase is required for the activation process. An inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase prevents its elimination and leads to G1 arrest. Mevalonate and its metabolite, geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, restore the inhibitory effect of pravastatin on the degradation of p27 and allow Cdk2 activation. By the addition of geranylgeranyl pyrophosphate, Rho small GTPase(s) are geranylgeranylated and translocated to membranes during G1/S progression. The restoring effect of geranylgeranyl pyrophosphate is abolished with botulinum C3 exoenzyme, which specifically inactivates Rho. These results indicate (i) among mevalonate metabolites, geranylgeranyl pyrophosphate is absolutely required for the elimination of p27 followed by Cdk2 activation; (ii) geranylgeranylated Rho small GTPase(s) promote the degradation of p27 during G1/S transition in FRTL-5 cells.
细胞周期蛋白依赖性激酶（Cdk）酶被激活后进入细胞周期的S期。在从G1期到S期的过程中，消除细胞周期蛋白依赖性激酶抑制剂蛋白p27Kip1是激活过程所必需的。3-羟基-3-甲基戊二酰辅酶A还原酶的抑制剂可阻止p27Kip1的消除并导致G1期停滞。甲羟戊酸及其代谢产物香叶基香叶基焦磷酸，但不是法尼基焦磷酸，可恢复普伐他汀对p27降解的抑制作用并使Cdk2激活。通过添加香叶基香叶基焦磷酸，Rho小GTP酶在G1/S进程中被香叶基香叶基化并转位到细胞膜。肉毒杆菌C3外切酶可消除香叶基香叶基焦磷酸的恢复作用，该酶可特异性地使Rho失活。这些结果表明：（i）在甲羟戊酸代谢产物中，香叶基香叶基焦磷酸是消除p27继而激活Cdk2所绝对必需的；（ii）香叶基香叶基化的Rho小GTP酶在FRTL-5细胞的G1/S转变过程中促进p27的降解。
