Abstract
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.
Highlights
Tubulin polymerization promoting protein 1 (Tppp1) regulates microtubule dynamics and cell growth
Tppp1 Inhibits Cell Proliferation—Dynamic rearrangement of the microtubule network is imperative for the transition of cells through the cell cycle phases and for cell proliferation
We demonstrate here that Rho-associated coiled-coil kinase (Rock)-mediated Tppp1 phosphorylation inhibits its regulation of the G1/S-phase transition, whereas Rock- and cyclin-dependent kinases (Cdks)-mediated phosphorylation are necessary to inhibit its mitotic regulatory activity
Summary
Tppp regulates microtubule dynamics and cell growth. Results: Tppp1-mediated inhibition of the G1/S-phase and the mitosis to G1-phase transitions are relieved by Rock and Cdk phosphorylation. 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 analysis of the role of Tppp during mitosis revealed that inhibition of its MT polymerizing and Hdac regulatory activities were necessary for cells to re-enter the G1-phase. During this investigation, we discovered that Tppp is a novel Cyclin B/Cdk (cyclin-dependent kinase) substrate and that Cdk phosphorylation of Tppp inhibits its MT polymerizing activity. Tppp Inhibits Cell Proliferation its inhibitory effect on the E2F transcription factor This partially activates E2F-mediated transcriptional up-regulation of genes including cyclin E, cyclin A, and Cdk. We show here that Rock- and Cdk-mediated phosphorylation of Tppp control cell cycle progression and cell proliferation
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