Aurora-A — A guardian of poles

Key Points

  • Aurora/Ipl1-related kinases are evolutionally conserved serine/threonine kinases that regulate mitotic progression in various organisms. Humans have three classes of Aurora kinases (A, B and C). Aurora-A and -B are ubiquitously expressed and regulate cell-cycle events from G2 to M phase.

  • Aurora-A is localized at centrosome during interphase, translocated to mitotic spindles in early mitotic phase and degraded after metaphase–anaphase transition. Activation of Aurora-A is required for mitotic entry, centrosome maturation, centrosome separation and chromosome alignment, and inactivation is also necessary for exit from mitosis.

  • Human Aurora-A is frequently amplified in various cancers. The levels of Aurora-A mRNA and protein are increased in those tumours and the overexpression of Aurora-A efficiently transforms immortalized rodent fibroblasts, indicating that Aurora-A is an oncoprotein.

  • Aurora-A kinase is activated by interaction with Ajuba and TPX2 during late G2 and mitotic phases, respectively.

  • Overexpression of Aurora-A induces abnormalities in G2 checkpoint and spindle checkpoint and cytokinesis failure. Those abnormalities lead to chromosome instability but are not sufficient for tumorigenesis in animal models. Additional changes such as p53 inactivation and expression of pro-survival proteins might be required for Aurora-A-mediated tumorigenesis.

  • Aurora-kinase inhibition effectively blocks cell growth and induces apoptosis in cancer cells. It might provide a new approach for the treatment of many human malignancies.

Abstract

The three human homologues of Aurora kinases (A, B and C) are essential for proper execution of various mitotic events and are important for maintaining genomic integrity. Aurora-A is mainly localized at spindle poles and the mitotic spindle during mitosis, where it regulates the functions of centrosomes, spindles and kinetochores required for proper mitotic progression. Recent studies have revealed that Aurora-A is frequently overexpressed in various cancer cells, indicating its involvement in tumorigenesis. What are the normal physiological roles of Aurora-A, how are these regulated and how might the enzyme function during tumorigenesis?

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Figure 1: Structure of human Aurora kinases.
Figure 2: Localization of Aurora-A and -B kinases during the cell cycle.
Figure 3: Molecular interactions required for centrosome maturation.
Figure 4: Diagram depicting the predicted tumorigenesis by Aurora-A overexpression.

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Acknowledgements

We thank T. Hirota, T. Sasayama, S. Iida, S. Kuninaka, T. Hara, N. Kunitoku, N. Araki and T. Mimori for helpful discussion. This work was supported by a grant for Cancer Research from the Ministry of Education, Science and Culture of Japan (H.S.) and 'Research for the Future' programme of the Japan Society for the Promotion of Science (H.S.).

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Correspondence to Hideyuki Saya.

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DATABASES

Entrez Gene

AIR-1

Aurora-A

Aurora-B

Aurora-C

CDC25B

CDK1

cyclin B1

MDM2

p53

RACGAP1

Stk6

TPX2

National Cancer Institute

bladder cancer

breast cancer

colon cancer

gastric cancer

ovarian cancer

pancreatic cancer

FURTHER INFORMATION

Chemical Genetic Analysis of Chromosome Instability

Glossary

LIM PROTEINS

LIM domains are modular protein-interaction motifs present in proteins with diverse functions. Ajuba has three LIM domains at the carboxyl terminus, and LIM-2 and LIM-3 domains are required for interaction with Aurora-A.

KINETOCHORE

Kinetochores are required for normal chromosome alignment. They provide a site for the attachment of spindle microtubules that allows generation of the force required for chromosome movement.

AMPHITELIC ATTACHMENT STATE

During mitosis, to achieve the proper segregation of replicated chromosomes, the two sister kinetochores on each chromosome need to attach to microtubules of opposite polarity.

CENP-A

CENP-A is a conserved variant of histone H3 that substitutes for this protein in the nucleosome core of centromeric chromatin. CENP-A is required for assembly of other kinetochore proteins and is required for chromosome alignment at the metaphase plate.

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Marumoto, T., Zhang, D. & Saya, H. Aurora-A — A guardian of poles. Nat Rev Cancer 5, 42–50 (2005). https://doi.org/10.1038/nrc1526

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