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Cell division

Mitotic kinases as regulators of cell division and its checkpoints

Abstract

Mitosis and cytokinesis are undoubtedly the most spectacular parts of the cell cycle. Errors in the choreography of these processes can lead to aneuploidy or genetic instability, fostering cell death or disease. Here, I give an overview of the many mitotic kinases that regulate cell division and the fidelity of chromosome transmission.

Key Points

Summary

  • An important rule of the cell cycle is that there should be no mitotic M phase without a proper S phase in which the chromosomes and centrosomes have been duplicated once only.

  • Mitosis can be divided into five stages: prophase, prometaphase, metaphase, anaphase and telophase. Cytokinesis (cell cleavage) occurs at the end of mitosis.

  • Mitotic progression requires that several checkpoints are silenced, the most prominent of which are the DNA structure checkpoints, and the spindle assembly and positioning checkpoints.

  • The regulation of mitosis relies mainly on phosphorylation and proteolysis, two intimately intertwined processes.

  • The main mitotic kinase is Cdk1. Activation of mammalian Cdk1 depends on dephosphorylation by Cdc25. Cdk1–cyclin complexes then phosphorylate numerous substrates necessary for nuclear envelope breakdown, centrosome separation, spindle assembly, chromosome condensation and Golgi fragmentation. Upon cyclin destruction, Cdk1 is inactivated, leading to mitotic exit.

  • Polo kinases regulate several stages of mitotic progression and associate transiently to many mitotic structures, including spindle poles, kinetochores, the midzone of the central spindle and the midbody. Some of their proposed substrates are Cdc25C, β-tubulin, APC/C subunits and the kinesin-related protein MKLP-1. The activity level of Polo kinases peaks during M phase, and they are degraded by the proteasome after exit from mitosis.

  • The NIMA-related kinase Nek2 is mainly involved in the control of centrosome structure during the mitotic cell cycle.

  • Aurora kinases are expressed in proliferating cells and overexpressed in some tumour cells. Similar to Polo kinases, they are regulated by phosphorylation and ubiquitin-dependent degradation. Aurora-A has its peak of activity before aurora-B, and its subcellular localization is also different: whereas aurora-A binds to centrosomes and the spindle apparatus from prophase until telophase, aurora-B is present at the midzone during anaphase, and in postmitotic bridges during telophase.

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Figure 1: A narrative of mitotic progression from the Cdk1 perspective.
Figure 2: Phosphorylation differentially regulates two forms of APC/C.
Figure 3: Checkpoints ordering progression through M phase.
Figure 4: The spindle assembly checkpoint.
Figure 5: Mitotic kinases regulating mitotic exit and cytokinesis.

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Acknowledgements

I thank F. Barr, P. Duncan, W. Earnshaw, A. Fry, P. Meraldi, J. Pines, H. Silljé and S. Wheatley for helpful comments on the manuscript, and P. Meraldi for generously providing immunofluorescence figures. My apologies go to all authors whose primary work could not be cited because of space constraints.

Author information

Authors and Affiliations

Authors

Related links

Related links

DATABASE LINKS

Cdk1

Polo

aurora

NIMA

retinoblastoma

E2F

Cdk2

cyclin A

cyclin E

Mps1p

Cdc25C

Wee1

Myt1

lamins

condensins

Golgi matrix components

APC/C

ubiquitin

securins

cyclins

Polo

Asp

Nek2

C-Nap1

Eg5

H1

H3

Ipl1p

Glc7p

stathmin

CENP-E

Ndc10p

ICENP

CENP-A

separase

cohesin

Cdc20

Cdh1

Plk1

BubR1

PKA

Cdc14p

Chk1

Bub1p

Bub3p

Mad1p

Mad2p

Mad3p

Bub2p

Tem1p

Sic1p

Swi5p

Plo1p

MKLP-1/Pavarotti

Mid1p

Cdc5p

survivin

FURTHER INFORMATION

Nigg lab homepage

ENCYCLOPEDIA OF LIFE SCIENCES

Mitosis

Glossary

OMNIS CELLULA E CELLULA

All cells are derived from cells.

MITOSIS

The process of nuclear division.

CYTOKINESIS

The process of cytoplasmic division.

SISTER CHROMATIDS

Duplicated chromosomes.

CENTROSOME

The main microtubule-organizing centre of animal cells.

MITOTIC SPINDLE

A highly dynamic bipolar array of microtubules that forms during mitosis or meiosis and serves to move the duplicated chromosomes apart.

CHECKPOINT

A point where the cell division cycle can be halted until conditions are suitable for the cell to proceed to the next stage.

SPINDLE POLE BODY

The yeast equivalent of the centrosome.

NUCLEAR LAMINA

A nuclear membrane-associated protein structure made up of lamin intermediate-filament proteins.

KINESIN

Microtubule-based molecular motor, most often directed towards the plus end of microtubules.

NUCLEAR ENVELOPE

Double membrane that surrounds the nucleus. The outer membrane is continuous with the endoplasmic reticulum.

γ-TUBULIN RING COMPLEXES

Ring-like multiprotein structures implicated in microtubule nucleation.

DYNEIN

Microtubule-based molecular motor that moves towards the minus end of microtubules.

RNA-MEDIATED INTERFERENCE

Process by which an introduced double-stranded RNA specifically silences the expression of genes through degradation of their cognate mRNA.

CATASTROPHE RATE

The frequency of transitions between rapid growth and shrinkage of microtubules.

KINETOCHORE

Specialized assembly of proteins that binds to a region of the chromosome called the centromere.

CENTROMERE

A region of a eukaryotic chromosome that is attached to the mitotic spindle.

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Nigg, E. Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol 2, 21–32 (2001). https://doi.org/10.1038/35048096

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