Regulation of the Action of Early Mitotic Inhibitor 1 on the Anaphase-promoting Complex/cyclosome by Cyclin-dependent Kinases

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2011 Apr 2

PMID 21454540

Citations 20

Authors

Yakir Moshe

Ortal Bar-On

Dvora Ganoth

Avram Hershko

Affiliations

Soon will be listed here.

Abstract

Cell cycle regulation is characterized by alternating activities of cyclin-dependent kinases (CDKs) and of the ubiquitin ligase anaphase promoting complex/cyclosome (APC/C). During S-phase APC/C is inhibited by early mitotic inhibitor 1 (Emi1) to allow the accumulation of cyclins A and B and to prevent re-replication. Emi1 is degraded at prophase by a Plk1-dependent pathway. Recent studies in which the degradation pathway of Emi1 was disrupted have shown that APC/C is activated at mitotic entry despite stabilization of Emi1. These results suggested the possibility of additional mechanisms other than degradation of Emi1, which release APC/C from inhibition by Emi1 upon entry into mitosis. In this study we report one such mechanism, by which the ability of Emi1 to inhibit APC/C is negatively regulated by CDKs. We show that in Plk1-inhibited cells Emi1 is stabilized and phosphorylated, that Emi1 is phosphorylated by CDKs in mitotic but not S-phase cell extracts, and that Emi1 phosphorylation by mitotic cell extracts or purified CDKs markedly reduces the ability of Emi1 to bind and to inhibit APC/C. Finally, we show that the addition of extracts from S-phase cells to extracts from mitotic cells protects Emi1 from CDK-mediated inactivation.

Citing Articles

The role of Fbxo5 in the development of human malignant tumors.

Gao J, Yang D, Cao R, Huang H, Ma J, Wang Z Am J Cancer Res. 2022; 12(4):1456-1464.

PMID: 35530293 PMC: 9077063.

APC/C: current understanding and future perspectives.

Yamano H F1000Res. 2019; 8.

PMID: 31164978 PMC: 6534075. DOI: 10.12688/f1000research.18582.1.

Posing the APC/C E3 Ubiquitin Ligase to Orchestrate Cell Division.

Watson E, Brown N, Peters J, Stark H, Schulman B Trends Cell Biol. 2018; 29(2):117-134.

PMID: 30482618 PMC: 6340778. DOI: 10.1016/j.tcb.2018.09.007.

EMI1 switches from being a substrate to an inhibitor of APC/C to start the cell cycle.

Cappell S, Mark K, Garbett D, Pack L, Rape M, Meyer T Nature. 2018; 558(7709):313-317.

PMID: 29875408 PMC: 6035873. DOI: 10.1038/s41586-018-0199-7.

CDK1 and PLK1 coordinate the disassembly and reassembly of the nuclear envelope in vertebrate mitosis.

de Castro I, Sales Gil R, Ligammari L, Di Giacinto M, Vagnarelli P Oncotarget. 2018; 9(8):7763-7773.

PMID: 29487689 PMC: 5814256. DOI: 10.18632/oncotarget.23666.

References

Reed S . Ratchets and clocks: the cell cycle, ubiquitylation and protein turnover. Nat Rev Mol Cell Biol. 2003; 4(11):855-64. DOI: 10.1038/nrm1246. View

Lu K, Liou Y, Zhou X . Pinning down proline-directed phosphorylation signaling. Trends Cell Biol. 2002; 12(4):164-72. DOI: 10.1016/s0962-8924(02)02253-5. View

Liu J, Grimison B, Lewellyn A, Maller J . The anaphase-promoting complex/cyclosome inhibitor Emi2 is essential for meiotic but not mitotic cell cycles. J Biol Chem. 2006; 281(46):34736-41. DOI: 10.1074/jbc.M606607200. View

Murray A . Recycling the cell cycle: cyclins revisited. Cell. 2004; 116(2):221-34. DOI: 10.1016/s0092-8674(03)01080-8. View

Sudakin V, Shteinberg M, Ganoth D, Hershko J, Hershko A . Binding of activated cyclosome to p13(suc1). Use for affinity purification. J Biol Chem. 1997; 272(29):18051-9. DOI: 10.1074/jbc.272.29.18051. View

Sumara I, Gimenez-Abian J, Gerlich D, Hirota T, Kraft C, de la Torre C . Roles of polo-like kinase 1 in the assembly of functional mitotic spindles. Curr Biol. 2004; 14(19):1712-22. DOI: 10.1016/j.cub.2004.09.049. View

Montagnoli A, Fiore F, Eytan E, Carrano A, Draetta G, Hershko A . Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation. Genes Dev. 1999; 13(9):1181-9. PMC: 316946. DOI: 10.1101/gad.13.9.1181. View

Guardavaccaro D, Kudo Y, Boulaire J, Barchi M, Busino L, Donzelli M . Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo. Dev Cell. 2003; 4(6):799-812. DOI: 10.1016/s1534-5807(03)00154-0. View

Lehman N, Tibshirani R, Hsu J, Natkunam Y, Harris B, West R . Oncogenic regulators and substrates of the anaphase promoting complex/cyclosome are frequently overexpressed in malignant tumors. Am J Pathol. 2007; 170(5):1793-805. PMC: 1854971. DOI: 10.2353/ajpath.2007.060767. View

10.

Lee H, Lee D, Oh S, Park H, Nam H, Kim J . Mouse emi1 has an essential function in mitotic progression during early embryogenesis. Mol Cell Biol. 2006; 26(14):5373-81. PMC: 1592703. DOI: 10.1128/MCB.00043-06. View

11.

Eldridge A, Loktev A, Hansen D, Verschuren E, Reimann J, Jackson P . The evi5 oncogene regulates cyclin accumulation by stabilizing the anaphase-promoting complex inhibitor emi1. Cell. 2006; 124(2):367-80. DOI: 10.1016/j.cell.2005.10.038. View

12.

Lenart P, Petronczki M, Steegmaier M, Di Fiore B, Lipp J, Hoffmann M . The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1. Curr Biol. 2007; 17(4):304-15. DOI: 10.1016/j.cub.2006.12.046. View

13.

Golan A, Yudkovsky Y, Hershko A . The cyclin-ubiquitin ligase activity of cyclosome/APC is jointly activated by protein kinases Cdk1-cyclin B and Plk. J Biol Chem. 2002; 277(18):15552-7. DOI: 10.1074/jbc.M111476200. View

14.

Di Fiore B, Pines J . Defining the role of Emi1 in the DNA replication-segregation cycle. Chromosoma. 2008; 117(4):333-8. DOI: 10.1007/s00412-008-0152-x. View

15.

Hershko A . Affinity purification of mitotic anaphase-promoting complex/cyclosome on p13Suc1. Methods Enzymol. 2005; 398:170-5. DOI: 10.1016/S0076-6879(05)98015-4. View

16.

Hershko A, Heller H, Elias S, Ciechanover A . Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown. J Biol Chem. 1983; 258(13):8206-14. View

17.

Grosskortenhaus R, Sprenger F . Rca1 inhibits APC-Cdh1(Fzr) and is required to prevent cyclin degradation in G2. Dev Cell. 2002; 2(1):29-40. DOI: 10.1016/s1534-5807(01)00104-6. View

18.

Aristarkhov A, Eytan E, Moghe A, Admon A, Hershko A, Ruderman J . E2-C, a cyclin-selective ubiquitin carrier protein required for the destruction of mitotic cyclins. Proc Natl Acad Sci U S A. 1996; 93(9):4294-9. PMC: 39529. DOI: 10.1073/pnas.93.9.4294. View

19.

Miller J, Summers M, Hansen D, Nachury M, Lehman N, Loktev A . Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor. Genes Dev. 2006; 20(17):2410-20. PMC: 1560415. DOI: 10.1101/gad.1454006. View

20.

Mayer A, Wilkinson K . Detection, resolution, and nomenclature of multiple ubiquitin carboxyl-terminal esterases from bovine calf thymus. Biochemistry. 1989; 28(1):166-72. DOI: 10.1021/bi00427a024. View