Cytoskeleton and Cancer Unit St. Vincent's Institute of Medical Research, University of Melbourne, 3065 Victoria, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, 3065 Victoria, Australia.
Cytoskeleton and Cancer Unit St. Vincent's Institute of Medical Research, University of Melbourne, 3065 Victoria, Australia.
J Biol Chem. 2013 Mar 15;288(11):7907-7917. doi: 10.1074/jbc.M112.441048. Epub 2013 Jan 25.
Tubulin polymerization promoting protein 1 (Tppp1) regulates microtubule (MT) dynamics via promoting MT polymerization and inhibiting histone deacetylase 6 (Hdac6) activity to increase MT acetylation. Our results reveal that as a consequence, Tppp1 inhibits cell proliferation by delaying the G1/S-phase and the mitosis to G1-phase transitions. We show that phosphorylation of Tppp1 by Rho-associated coiled-coil kinase (Rock) prevents its Hdac6 inhibitory activity to enable cells to enter S-phase. Whereas, our analysis of the role of Tppp1 during mitosis revealed that inhibition of its MT polymerizing and Hdac6 regulatory activities were necessary for cells to re-enter the G1-phase. During this investigation, we also discovered that Tppp1 is a novel Cyclin B/Cdk1 (cyclin-dependent kinase) substrate and that Cdk phosphorylation of Tppp1 inhibits its MT polymerizing activity. Overall, our results show that dual Rock and Cdk phosphorylation of Tppp1 inhibits its regulation of the cell cycle to increase cell proliferation.
微管相关蛋白 1（Tppp1）通过促进微管聚合和抑制组蛋白去乙酰化酶 6（Hdac6）活性来增加微管乙酰化，从而调节微管动力学。我们的结果表明，Tppp1 通过延迟 G1/S 期和有丝分裂到 G1 期的转变来抑制细胞增殖。我们表明，Rho 相关卷曲螺旋激酶（Rock）对 Tppp1 的磷酸化可防止其对 Hdac6 的抑制活性，使细胞进入 S 期。然而，我们对 Tppp1 在有丝分裂过程中的作用的分析表明，抑制其微管聚合和 Hdac6 调节活性对于细胞重新进入 G1 期是必要的。在这项研究中，我们还发现 Tppp1 是一种新型的周期蛋白 B/Cdk1（细胞周期蛋白依赖性激酶）底物，并且 Cdk 对 Tppp1 的磷酸化抑制其微管聚合活性。总的来说，我们的结果表明，Tppp1 的双重 Rock 和 Cdk 磷酸化抑制其对细胞周期的调节，从而增加细胞增殖。
