Aurora A, mitotic entry, and spindle bipolarity

Abstract

The kinase Aurora-A (Aur-A), which is enriched at centrosomes, is required for centrosome maturation and accurate chromosome segregation, and recent work implicates centrosomes as sites where the earliest activation of cyclin B1-cdc2 occurs. Here, we have used Xenopus egg extracts to investigate Aur-A's contribution to cell cycle progression and spindle morphology in the presence or absence of centrosomes. We find that addition of active Aur-A accelerates cdc2 activation and mitotic entry. Depletion of endogenous Aur-A or addition of inactive Aur-A, which lead to monopolar spindles, delays but does not block mitotic entry. These effects on timing and spindle structure do not require the presence of centrosomes or chromosomes. The catalytic domain alone of Aur-A is sufficient to restore spindle bipolarity; additional N-terminal sequences function in mitotic timing.Aurora kinases ͉ G2͞M transition ͉ mitosis

Targeted disruption of Aurora A causes abnormal mitotic spindle assembly, chromosome misalignment and embryonic lethality

“…It is plausible that initial cell divisions in the null embryos are facilitated by the presence of a low amount of maternal protein since the Unigene cluster database reveals existence of murine Aurka transcript (Mm 249363) in oocyte and zygote. Additionally, the presence of a relatively elevated number of cells in mitosis in the null embryos indicate that mitosis may be initiated with a delay rather than inhibited in absence of Aurora A as has been reported in case of Xenopus early embryonic cell cycles investigated with egg extracts depleted of endogenous Aurora A (Liu and Ruderman, 2006;Satinover et al, 2006). Aberrant spindle assembly is expected due to impaired formation of k fibers requiring active Aurora A complex with spindle assembly factors, such as TPX2 and HURP, among others (Gruss et al, 2001;Koffa et al, 2006;Sillje et al, 2006;Tulu et al, 2006).…”

“…Identification of microtubule-associated proteins as substrates of Aurora A (Yu et al, 2005;Koffa et al, 2006) as well as their localization on k fibers in prometaphase human cells (Sillje et al, 2006) indicates that Aurora A forms complex with mitotic spindle assembly factors in the organization of the spindle microtubules. Additionally, while silencing of Aurora A has been reported to cause delay or block in mitotic entry (Marumoto et al, 2002;Hirota et al, 2003;Du and Hannon, 2004;Satinover et al, 2006), accelerated initiation of mitosis in presence of active Aurora A has also been observed (Ma et al, 2003;Liu and Ruderman, 2006). These effects may, in part, be explained by the reported role of Aurora A in facilitating expression and activation of critical mitosis regulators cyclin B and Cdc25B (Mendez et al, 2000;Tay et al, 2000;Dutertre et al, 2004).…”

VX-680 Inhibits Aurora A and Aurora B Kinase Activity in Human Cells

“…24,25 We next turned our attention to two putative Aurora A substrates in VX-680-treated cells. The phosphorylation of Aurora A substrates is undetectable in an asynchronous cell population, but Aurora A becomes phosphorylated and activated on Thr288 in mitosis, [26][27][28] when Aurora A phosphorylates the centrosomal protein TACC3/ maskin on Ser558 (human numbering) in both human and Xenopus systems. 10 As shown in Figure 2E, the Aurora B inhibitor ZM447439 was unable to block the phosphorylation of either Aurora A or TACC3 in the presence of nocodazole, consistent with its specificity for Aurora B inhibition at this concentration.…”

Aurora‐A activation, correlated with hypoxia‐inducible factor‐1α, promotes radiochemoresistance and predicts poor outcome for nasopharyngeal carcinoma

“…Aurora-A kinase is essential in ensuring centrosome segregation and spindle formation. (19,20) In tumors, aberrant expression of Aurora-A was negatively correlated with tumor stage, and lymph node as well as distant metastasis. (30,33) Given its importance in tumor initiation and progression, targeting of Aurora-A might to be a novel therapeutic selection for cancer treatment.…”

“…(19,20) Overexpression of Aurora-A caused aberrant centrosome amplification, multipolar spindle structure, and aneuploidy. (21)(22)(23) Moreover, the malignant phenotype of Aurora-A might be ascribed to its interaction with several key molecular regulators, including Ajuba, p53, hypoxia-inducible factor-1a (HIF-1a), and TPX2.…”