Abstract
Aurora kinases belong to a conserved family of serine/threonine kinases key regulators of cell cycle progression. Aurora-A and Aurora-B are expressed in somatic cells and involved mainly in mitosis while Aurora-C is expressed during spermatogenesis and oogenesis and is involved in meiosis. Aurora-C is hardly detectable in normal somatic cells. However all three kinases are overexpressed in many cancer lines. Aurora-A possesses an oncogenic activity while Aurora-B does not. Here we investigated whether Aurora-C possesses such an oncogenic activity. We report that overexpression of Aurora-C induces abnormal cell division resulting in centrosome amplification and multinucleation in both transiently transfected cells and in stable cell lines. Only stable NIH3T3 cell clones overexpressing active Aurora-C formed foci of colonies when grown on soft agar, indicating that a gain of Aurora-C activity is sufficient to transform cells. Furthermore, we reported that NIH-3T3 stable cell lines overexpressing Aurora-C induced tumour formation when injected into nude mice, demonstrating the oncogenic activity of enzymatically active Aurora kinase C. Interestingly enough tumor aggressiveness was positively correlated with the quantity of active kinase, making Aurora-C a potential anti-cancer therapeutic target.
Highlights
Aurora kinases belong to a conserved family of serine/threonine kinases that are pivotal to the successful execution of cell division
Our results demonstrate that the overexpression of active Aurora kinase C induces centrosome amplification and polyploidy, defects frequently observed in cancers cells
We found more than 90% of abnormal metaphase and more than 85% of both lagging chromosomes and cytokinesis defects in Feulgen staining of tumours induced by GFP-aurC-WT or GFP-aurC-CA (Figure 5I)
Summary
Aurora kinases belong to a conserved family of serine/threonine kinases that are pivotal to the successful execution of cell division. The three members of the mammalian family, besides being implicated as mitotic regulators, have generated significant interest in the cancer research field due to their elevated expression profiles detected in many human cancers [2,3,4,5]. Aurora-A mRNA, protein expression levels and kinase activity are cell cycle regulated, low in G1/S phase, peaking in G2/M and dropping upon mitotic exit into the G1 [6,7]. Aurora-A displays dynamic subcellular localization: from duplicated centrosomes at the end of S phase to mitotic spindle poles from prophase through telophase. Activation of centrosomal Aurora-A at late G2 phase is essential for centrosome maturation and mitotic entry.
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