Abstract
The NCI-60 cell line panel is the most extensively characterized set of cells in existence, and has been used extensively as a screening tool for drug discovery. Previously, the potential of this panel has not been applied to the fundamental cellular processes of chromosome segregation. In the current study, we used data from multiple microarray platforms accumulated for the NCI-60 to characterize an expression pattern of genes involved in kinetochore assembly. This analysis revealed that 17 genes encoding the constitutive centromere associated network of the kinetochore core (the CCAN complex) plus four additional genes with established importance in kinetochore maintenance (CENPE, CENPF, INCENP, and MIS12) exhibit similar patterns of expression in the NCI-60, suggesting a mechanism for co-regulated transcription of these genes which is maintained despite the multiple genetic and epigenetic rearrangements accumulated in these cells (such as variations in DNA copy number and karyotypic complexity). A complex group of potential regulatory influences are identified for these genes, including the transcription factors CREB1, E2F1, FOXE1, and FOXM1, DNA copy number variation, and microRNAs has-miR-200a, 23a, 23b, 30a, 30c, 27b, 374b, 365. Thus, our results provide a template for experimental studies on the regulation of genes encoding kinetochore proteins, the process that, when aberrant, leads to the aneuploidy that is a hallmark of many cancers. We propose that the comparison of expression profiles in the NCI-60 cell line panel could be a tool for the identification of other gene groups whose products are involved in the assembly of organelle protein complexes.
Highlights
Chromosome segregation in eukaryotes requires a multi-protein structure termed the kinetochore, which assembles on centromeric DNA to mediate both the binding of spindle microtubules to chromosomes and chromosome movement
We propose that the comparison of expression profiles in the National Cancer Institute 60 cell line panel (NCI-60) cell line panel could be a tool for the identification of other gene groups whose products are involved in the assembly of organelle protein complexes
The inner kinetochore that is apposed to centromeric DNA is essential for kinetochore assembly
Summary
Chromosome segregation in eukaryotes requires a multi-protein structure termed the kinetochore, which assembles on centromeric DNA to mediate both the binding of spindle microtubules to chromosomes and chromosome movement. The inner kinetochore that is apposed to centromeric DNA is essential for kinetochore assembly. The centromere-specific histone H3 variant CENPA localizes in the inner plate and functions in the early organization of centromeric chromatin structure during interphase [2,3]. Other kinetochore proteins interact with CENPA-containing nucleosomes, leading to the assembly of a functional kinetochore. About 90 kinetochore proteins have been identified in humans [4,5,6]. The proteins of this complex are recruited to the kinetochore at different stages of mitosis
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