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Evolutionarily conserved developmental pathways

Cell cycle 7: Aurora B, regulated by chromosomal passenger proteins, coordinates reorganization of cellular components during mitosis

The chromosomal passenger complex (CPC) has emerged as a key player in mitosis, with important roles in chromatin modifications, kinetochore-microtubule interactions, chromosome bi-orientation and stability of the bipolar spindle, mitotic checkpoint function, assembly of the central spindle and cytokinesis. The inner centromere protein (Incenp; a subunit of this complex) is thought to regulate the Aurora B kinase and target it to its substrates. To explore the roles of the passenger complex in a developing multicellular organism, a genetic screen was performed looking for new alleles and interactors of Drosophila Incenp. A new null allele of Incenp has been isolated that has allowed a study of the functions of the chromosomal passengers during development. Homozygous incenpEC3747 embryos show absence of phosphorylation of histone H3 in mitosis, failure of cytokinesis and polyploidy, and defects in peripheral nervous system development. These defects are consistent with depletion of Aurora B kinase activity. In addition, the segregation of the cell-fate determinant Prospero in asymmetric neuroblast division is abnormal, suggesting a role for the chromosomal passenger complex in the regulation of this process (Chang, 2006).

The CPC is a complex of one enzymatic subunit, the Aurora B kinase (Ipl1 in S. cerevisiae and AIR-2 in C. elegans), and three regulatory subunits, the inner centromere protein INCENP (Sli15 in S. cerevisiae and ICP-1 in C. elegans), Survivin (Bir1 in S. cerevisiae, BIR-1 in C. elegans - probable Drosophila homolog CG12265), and Borealin (Dasra-B in Xenopus and CSC-1 in C. elegans; see Drosophila Borealin-related)). Aurora B belongs to a conserved family of Ser-Thr protein kinases comprising also Aurora A and C that are crucial regulators of mitosis in eukaryotes. The ever increasing list of Aurora B substrates includes the mitotic histone variant CENP-A, the mitotic centromere-associated kinesin MCAK, the intermediate filament protein vimentin (Goto et al., 2003), and the microtubule motor protein Mklp1 at the central spindle and midbody. The current view is that, in general, the targeting of Aurora B to the right substrates at the right place and time is crucial for cell division. This regulation is achieved by the assembly of the kinase with the other passenger components INCENP, Survivin, and Borealin (Jeyaprakash, 2007).

During mitosis, replicated chromosomes segregate equally to the two daughter cells on a complex molecular scaffold -- the mitotic spindle. Formation of the condensed mitotic chromosomes and the spindle involves reorganization of components of the cell nucleus and cytoskeleton, with changes occurring in different domains of the mitotic cell, in a coordinated sequence. These changes are triggered by the action of a number of protein kinases, including Cdk1:cyclin B, Plk1, and the Aurora kinases. Aurora B kinase is a chromosomal passenger protein that associates with chromosomes during the early stages of mitosis and transfers from chromosomes to the central spindle and cell cortex at the onset of anaphase. It is thus a strong candidate for an activity that triggers changes in different domains of the mitotic cell at different times during mitosis (Chang, 2006 and references therein).

The chromosomal passenger proteins are present in a complex that includes Incenp (inner centromere protein), Aurora B kinase, and Borealin). A fifth protein, telophase disc 60 (TD-60), appears to be functionally linked to the complex, but is not stably associated with it. Yeast homologs of borealin or TD-60 have yet to be identified. These five proteins are all mutually interdependent for their localization during mitosis, further supporting the notion that their functions are also interdependent. The chromosomal passengers are required for a number of key functions during mitosis, including chromatin modifications, regulation of kinetochore-microtubule interactions, chromosome bi-orientation and stability of the bipolar spindle, mitotic checkpoint function, assembly of the central spindle and cytokinesis (Chang, 2006 and references therein).

It is currently thought that the various components of the chromosomal passenger complex target and regulate Aurora B kinase activity. Incenp binds to Aurora B kinase through its highly conserved C-terminal IN-BOX motif. Incenp is phosphorylated by Aurora B kinase, and this activates the kinase through a positive-feedback loop. In addition, because Incenp is a microtubule-binding protein that also has a well-defined centromere-targeting domain at its N-terminus, it was suggested to have a role in targeting the kinase to particular locations within the mitotic cell (Chang, 2006 and references therein).

Genetic analysis of the chromosomal passenger complex in higher eukaryotes has thus far been limited to the mouse, where knockouts of survivin and Incenp have been described. Genes encoding survivin and Incenp are essential, and homozygous-null embryos die early, at the 32-64-cell stage. Survivin-null embryos have high levels of failed cytokinesis and polyploidy. Incenp-null embryos are characterized by the absence of discernible metaphase or anaphase stages, absence of midbodies, multinucleated cells, multipolar mitotic spindles, micronuclei, abnormal microtubule bundling and chromatin bridges. However, in both cases, the early death of the embryos made it difficult to observe a sufficient number of mitotic cells to perform a thorough analysis of the phenotype (Chang, 2006 and references therein).

The function of Incenp was investgated in normal cells and tissues during development of Drosophila. Incenp is essential for phosphorylation of histone H3 on Ser10, and also for cytokinesis in developing neurons. In addition to these defects, abnormalities were observed in the segregation of cell-fate determinants during neuroblast division; this suggests a role for the passengers in the regulation of asymmetric cell division (Chang, 2006).

date revised: 2 January 2008 

Developmental Pathways conserved in Evolution

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