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    • GDC-0449 Aurora A overexpression is also related to the acti

    2023-09-18

    Aurora-A overexpression is also related to the activation of NF-κB, a potent anti-apoptotic effector that may play a role in preventing apoptosis in cancer GDC-0449 [18]. These data show that we are still at the beginning of unraveling the complex mechanism by which these gene products and proteins interfere and interact. Fig. 1 gives an overview of Aurora-A functions and interactions.
    Aurora-B The Aurora-B gene is located at chromosome17p13.1 and like Aurora-A, Aurora-B kinase is overexpressed in tumor cells. The Aurora-B kinase is a chromosome passenger protein that localizes to the kinetochores from prophase to metaphase and relocates to the central spindle and the midbody in cytokinesis [19]. During mitosis, Aurora-B plays a critical role in chromosome attachment and biorientation, indicated by the fact that Hesperadin, a known inhibitor of Aurora-B, increased the incidence of mal-oriented chromosomes [20]. Aurora-B has three distinct but related functions; it is a histone kinase involved in phosphorylation of chromatin proteins, i.e. histone H3, a spindle checkpoint kinase and a cytokinesis kinase [2]. In mammalian cells Aurora-B is part of a chromosome passenger complex also containing inner centromere protein (INCENP), borealin and survivin. INCENP and survivin have both regulatory and targeting functions and are phosphorylated by Aurora-B in vitro[6]. Borealin is an Aurora-B substrate but not a kinase activator. It appears to target the Aurora-B to centromeres [21]. The role of survivin as a supposed key inhibitor of apoptosis is subject to criticism and debate because of conflicting study results. It is postulated that lack of survivin, as part of the Aurora-B complex, can negatively affect spindle checkpoint formation to an extent that can lead to mitotic catastrophe, which under the appropriate conditions can lead to apoptosis [6]. The exact role of survivin however remains the subject of intense research. Another important factor in the regulation and activity of the chromosomal passenger complex is Cullin 3-based ligase (Cul3). Cul3 is, in a complex with adaptors KLHL9 and KLHL13, required for correct chromosome alignment, correct midbody formation, and completion of cytokinesis [22]. Aurora-B is ubiquitilated in a Cul3-dependent manner in vivo indicating that the Cul3/KLHL9/KLHL13 E3 ligase might control the dynamic behavior of Aurora-B and thereby coordinates mitotic progression and completion of cytokinesis. The mechanism by which Aurora-B can correct biorientation failures in mammalian cells remains subject of research. A major breakthrough came with the identification of MCAK (mitotic centromere-associated kinesin). MCAK is an Aurora-B substrate in vitro and in vivo and is required for chromosome gathering, biorientation, bipolar spindle formation and chromosome movement during anaphase [23]. Aurora-B phosphorylates MCAK leading to inactivation of the microtubule depolymerase catalytic activity of MCAK and targeting of MCAK to the kinetochores [24], [25], [26]. Incorrect kinetochores-spindle attachments can then be corrected by local activation of the microtubule depolymerase activity of MCAK by an activator such as cdc14 [27] amongst others. Also PPI, located at the outer kinetochore [28], dephosphorylates Aurora-B substrates [29], suggesting that MCAK activity is modulated by phosphorylation and dephosphorylation according to the specific time during the cell cycle and location of MCAK in the process of chromosome alignment, bipolar spindle formation and anaphase chromosome movement. These suggestions were recently confirmed when it was shown that MCAK association with chromosome arms is promoted by phosphorylation of T95 on MCAK by Aurora-B, while phosphorylation of S196, also by Aurora-B, promotes dissociation from the chromosome arms [30]. Furthermore, targeting of MCAK to centromeres requires Aurora-B mediated phosphorylation of S110, whereas dephosphorylation of T95 increases the binding of MCAK to the centromeres. Given the importance of MCAK in Aurora-B activity, MCAK localization and phosphorylation may prove to be useful surrogate markers for Aurora-B inhibition.