The human Mixed lineage leukemia 5 ( MLL5) gene is located on the chromosome 7q22, which is commonly deleted in acute myeloid leukemia (AML) and therapy-induced leukemia ( Emerling et al., 2002). Depletion of any member of the CPC by RNA interference delocalizes the complex, renders it unstable and disrupts mitotic progression ( Honda et al., 2003 Klein et al., 2006). Within the CPC, the four subunits interact extensively, and the interactions not only regulate the centromere targeting of the complex, but also maintain the stability of CPC. One of the key events orchestrated by CPC is the correction of kinetochore-MT attachment errors, which is dependent on the kinase activity of Aurora-B by promoting the turnover of improper kinetochore-MT attachments ( Vader et al., 2006). At anaphase and telophase, CPC transfers to the spindle midzone, the equatorial cortex and to the midbody, where it is essential for the cytoplasmic division. CPC initially localizes to the chromosome arms to control the chromosome structure and organization, subsequently concentrates on the inner centromeres to promote the kinetochore-microtubule (MT) interactions ( Ruchaud et al., 2007). The expression of CPC is cell cycle dependent, with minimal expression in G1/S, and gradually increases during G2 phase and peaks at M phase ( Honda et al., 2003 Terada et al., 1998 Zhao et al., 2000). It comprises the Aurora-B kinase and three non-enzymatic regulatory subunits, Survivin, Borealin and INCENP ( Gassmann et al., 2004 Ruchaud et al., 2007). Human chromosomal passenger complex (CPC) is a critical regulator of chromosome segregation during mitosis. High-throughput genomic profiling study reveals that most human cancers are aneuploid and chromosomally unstable ( Beroukhim et al., 2010). Defects in mitotic fidelity cause DNA segregation errors and result in chromosome instability, which plays a causal role in tumorigenesis and relapse ( Baker et al., 2009 Sotillo et al., 2010). Mitosis is a highly regulated process that ensures the accurate segregation of duplicated chromosomes to the daughter cells. Collectively, our results suggest that MLL5 functionally interacts with Borealin, facilitates the expression of CPC, and hence contributes to mitotic fidelity and genomic integrity. Moreover, the mitotic defects in MLL5-depleted cells were rescued by overexpression of FLAG-MLL5, but not by a FLAG-MLL5 mutant that did not contain the central domain. Biochemical analyses further demonstrated that the central domain of MLL5 interacted with the C-terminus of Borealin, and the interaction is essential to maintain the stability of Borealin. Mechanistic studies revealed that the chromosomal passenger complex (CPC), which plays a key role in chromosomal bi-orientation, was delocalized from the inner centromere region because of proteasome-mediated degradation in MLL5-depleted cells.

SiRNA-mediated downregulation of MLL5 caused improper chromosome alignment at metaphase and resulted in failure of DNA segregation and cytokinesis. In this paper, the function of MLL5 in mitotic regulation is further explored. We have shown previously that phosphorylation of MLL5 by Cdk1 is required for mitotic entry. Mixed lineage leukemia 5 (MLL5) is a versatile nuclear protein associated with many cellular events.

Cpc 2000 prompter software