Chromosome Dynamics: New Light on Aurora B Kinase Function Dispatch

The Aurora kinases are a family of cell-cycle kinases whose activity peaks in mitosis; in higher eukaryotes, the kinases come in three related classes: Aurora A, B and C. The levels of these kinases are elevated in some human cancers, and overexpression of any one can cause cell transformation [1]. The regulation and functions of these kinases are thus of considerable interest. Aurora B kinases are ‘chromosomal passenger’ proteins, which are found in cells in a complex with INCENP and Survivin. Together, these proteins first localize along the length of the chromosome during prophase, and become concentrated at the inner centromere region during prometaphase. During anaphase, these proteins leave the chromosome and localize to the central spindle. The localization of the chromosomal passenger complex and the phenotypes of mutants suggested that this complex is involved in chromosome structure and alignment, as well as in coordinating anaphase and cytokinesis [2]. A flurry of recent papers have provided further insights into the role of the Aurora B kinase in mitosis. MurataHori and Wang [3] used the kinase-dead mutant Aurora B (K-R) to perturb Aurora B function in mammalian NRK tissue cells. High levels of expression of this dominantnegative protein caused multiple defects in the mitotic machinery. These defects include a microtubule-dependent loss of the motor proteins dynein and CENP-E from kinetochores; loss of kinetochore attachment to microtubules; and exit from mitosis without anaphase or cytokinesis. In cells expressing Aurora B (K-R), the spindle microtubules formed a single central bundle with unattached chromosomes clustered on either side, rather than a wild-type spindle with bioriented chromosomes at the spindle equator. The loss of dynein and CENP-E, as well as Mad2 [4], from kinetochores in these cells indicates that Aurora B kinase plays a major role in the kinetochore assembly pathway in mammalian cells. Only one mammalian kinetochore target for the Aurora B kinase is known: CENP-A, a histone H3 variant. However, mutations preventing CENP-A phosphorylation do not disrupt the kinetochore or mitosis, but they do prevent completion of cytokinesis [5]. Kallio et al. [6] used a kinase-inhibiting Aurora B antibody to interfere with Aurora B function in Xenopus XTC cells or egg extracts. They observed milder defects in chromosome congression and spindle morphology. While many chromosomes aligned at the metaphase plate, some chromosomes failed to align and remained near the poles. The spindles in antibody-inhibited cells had kinetochore fibers as well as markedly extended astral microtubules. Despite the defects in chromosome congression, the cells exited mitosis without anaphase or cytokinesis. Antibody inhibition in Xenopus egg extracts demonstrated that Aurora B is required for both the establishment and maintenance of the spindle checkpoint. The failure of all chromosomes to biorient, and the increased stability of astral microtubules, also suggest that the kinase activity of Aurora B promotes microtubule dynamics. Kaitna et al. [7] examined the organization of the holocentric kinetochores in cells of the Caenorhabditis elegans after disruption of AIR-2, the nematode Aurora B homolog, by RNA interference (RNAi). In the Aurora B-depleted embryos, localization of kinetochore components appeared normal at prometaphase, appearing as two discrete bands flanking each chromosome as in wild type. But at metaphase, the kinetochore was disorganized, with components appearing throughout the chromatin. Chromosome segregation in anaphase was poor, but kinetochores appeared attached by microtubules to spindle poles. The authors propose that the chromosomes may exhibit disorganized kinetochores because of ‘merotelic’ attachment, with individual kinetochores attached to microtubules from opposite poles. If one sister kinetochore becomes attached to both spindle poles, the kinetochore would be twisted and the chromosomes would align along the axis of the spindle and not segregate properly in anaphase as observed. Merotelic kinetochore attachment might contribute to the lagging chromosomes seen during anaphase in Drosophila cultured cells depleted of either INCENP or Aurora B [8]. Merotelic kinetochore attachment is a major mechanism that results in errors in chromosome segregation in mammalian tissue cells [9]. Thus, another apparent key mitotic function of the Aurora B kinase is to prevent or correct improper kinetochore microtubule attachment. More than 30 years ago, Nicklas and Koch [10] showed that tension at kinetochores promotes stable microtubule attachment. The work of Kaitna et al. [7] along with recent studies [11,12] on the function of the single budding yeast Aurora ortholog Ipl1, now provide a foundation for understanding the molecular basis of how the stability of microtubule attachment is regulated. The yeast studies [11,12] show that Ipl1 corrects mis-orientation of kinetochores by destabilizing microtubule attachment at kinetochores under low tension. An attractive hypothesis has been Current Biology, Vol. 12, R458–R460, July 9, 2002, ©2002 Elsevier Science Ltd. All rights reserved. PII S0960-9822(02)00945-4