Aurora-A: the maker and breaker of spindle poles

Abstract

The gene encoding the Aurora-A protein kinase is located in the 20q13 breast cancer amplicon and is also overexpressed in colorectal, pancreatic and gastric tumours. Although Aurora-A may not be a bona fide oncoprotein in humans, it is a promising drug target in cancer therapy. Thus, it is surprising that so little is known of its role in normal cells. The primary function of Aurora-A is to promote bipolar spindle assembly, but the molecular details of this process remained obscure until recently. The discovery of several novel Aurora-A-binding proteins and substrates has implicated Aurora-A in centrosome maturation and separation, acentrosomal and centrosomal spindle assembly, kinetochore function, cytokinesis and in cell fate determination. Here we discuss recent advances in determining the early mitotic role of Aurora-A, with a strong emphasis on its function at the mitotic spindle poles.

Mitotic drivers—inhibitors of the Aurora B Kinase

“…However, in 2006 it was it shown using a dual Aurora A/B inhibitor, ZM3 that it was possible to suppress Aurora A kinase activity in cells with a small molecule [30]. Encouragingly, this resulted in a monopolar spindle phenotype, confirming the observations derived from model organisms [25]. Subsequently, a selective Aurora A inhibitor has been described, namely MLN8054.…”

“…The Aurora family of protein kinases is conserved from yeast to man [for recent reviews see [25][26][27]]. While budding and fission yeast express a single Aurora kinase, Ipl1 and Ark1 respectively, higher eukaryotes express at least two Aurora kinases, A and B, with mammals expressing a third, Aurora C. The founder member of the family, Drosophila Aurora A, was identified because Aurora mutations caused abnormal mitoses, largely due to a failure in centrosome separation yielding monopolar spindles [28].…”

Repression of cancer cell senescence by PKCι

“…As an alternate means to impairing mitosis, the effects of aurora kinase inhibition on senescence were assessed, both in the absence and presence of PKCi depletion. The aurora kinases are known to have a central role in the control of mitosis (Barr and Gergely, 2007). The pan-aurora kinase inhibitor VX-680 was used for these experiments (Harrington et al, 2004).…”

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

“…Whereas, other non-centrosomal proteins involved in spindle assembly associate only temporary to centrosomes during mitosis, such as Nuclear Mitotic Apparatus protein (NuMA), which has multiple functions in spindle assembly including cross-linking microtubules (bundling) into the correct organization (Sun and Schatten, 2006). Particularly noteworthy is the presence of Cdk1-Cyclin B, Plk1 (Polo-like kinase-1) and Aurora A mitotic cell cycle regulatory proteins within mitotic centrosomes (Jackman et al, 2003;Golsteyn et al, 1995;Tsvetkov et al, 2003;Barr and Gergely 2007). These centrosomal factors play important roles in spindle formation.…”