den Hollander J, Rimpi S, Doherty JR, Rudelius M, Buck A, Hoellein A et al.. Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood 116: 1498-1505

III Medical Department, Technische Universität München, Munich, Germany.
Blood (Impact Factor: 10.45). 09/2010; 116(9):1498-505. DOI: 10.1182/blood-2009-11-251074
Source: PubMed


Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B-cell lymphomas in both mice and humans. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, whereas Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization, and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly, apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function.

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Available from: Joanne Doherty, Nov 04, 2014
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    • "Recently, much work is focused on a clear understanding of the function of the MYC gene because it is overexpressed in as many as about 70% of cancers, which leads to a state of hyperproliferation and cancer progression. The search for compounds having a regulating effect on the amplification of this gene has been identified as a new therapeutic target [14–19]. "
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    • "Notably, >90% of cancers overexpress or overactivate AURKA at some level, and this outcome can be mediated directly by oncogene expression (den Hollander et al. 2010; Lens et al. 2010). According to our studies, accentuated AURKA–PLK1 pathway activity may promote replication fork collapse and an increased dependence on ATR function. "
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    ABSTRACT: The ATR-CHK1 axis stabilizes stalled replication forks and prevents their collapse into DNA double-strand breaks (DSBs). Here, we show that fork collapse in Atr-deleted cells is mediated through the combined effects the sumo targeted E3-ubiquitin ligase RNF4 and activation of the AURKA-PLK1 pathway. As indicated previously, Atr-deleted cells exhibited a decreased ability to restart DNA replication following fork stalling in comparison with control cells. However, suppression of RNF4, AURKA, or PLK1 returned the reinitiation of replication in Atr-deleted cells to near wild-type levels. In RNF4-depleted cells, this rescue directly correlated with the persistence of sumoylation of chromatin-bound factors. Notably, RNF4 repression substantially suppressed the accumulation of DSBs in ATR-deficient cells, and this decrease in breaks was enhanced by concomitant inhibition of PLK1. DSBs resulting from ATR inhibition were also observed to be dependent on the endonuclease scaffold protein SLX4, suggesting that RNF4 and PLK1 either help activate the SLX4 complex or make DNA replication fork structures accessible for subsequent SLX4-dependent cleavage. Thus, replication fork collapse following ATR inhibition is a multistep process that disrupts replisome function and permits cleavage of the replication fork.
    Full-text · Article · Oct 2013 · Genes & development
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    • "Furthermore, there is evidence that c-Myc is involved in polyploidisation of normal mouse hepatocytes; in particular it was shown that c-Myc accelerates hepatic ploidy in transgenic mouse models [112]. c-Myc also up-regulates Aurora B kinase [113] which is implicated in the maintenance of the malignant state and in mitotic slippage [48]; all effects which could contribute to the induction and maintenance of reversible polyploidy. Therefore, the switch to a glycolytic metabolism involving constitutional activation of c-Myc can be suggested as a key molecular event linking reversible polyploidy to stemness, immortality, and likely EMT phenotype of depolyploidised descendants and as a means of shifting from senescence towards cancer progression. "
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