Topoisomerase IIα Binding Domains of Adenomatous Polyposis Coli Influence Cell Cycle Progression and Aneuploidy

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Issue Date
2010-04-02Author
Wang, Yang
Coffey, Robert J.
Osheroff, Neil
Neufeld, Kristi L.
Publisher
Public Library of Science
Type
Article
Article Version
Scholarly/refereed, publisher version
Rights
©2010 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Show full item recordAbstract
Background
Truncating mutations in the tumor suppressor gene APC (Adenomatous Polyposis Coli) are thought to initiate the majority of colorectal cancers. The 15- and 20-amino acid repeat regions of APC bind β-catenin and have been widely studied for their role in the negative regulation of canonical Wnt signaling. However, functions of APC in other important cellular processes, such as cell cycle control or aneuploidy, are only beginning to be studied. Our previous investigation implicated the 15-amino acid repeat region of APC (M2-APC) in the regulation of the G2/M cell cycle transition through interaction with topoisomerase IIα (topo IIα).
Methodology/Principal Findings
We now demonstrate that the 20-amino acid repeat region of APC (M3-APC) also interacts with topo IIα in colonic epithelial cells. Expression of M3-APC in cells with full-length endogenous APC causes cell accumulation in G2. However, cells with a mutated topo IIα isoform and lacking topo IIβ did not arrest, suggesting that the cellular consequence of M2- or M3-APC expression depends on functional topoisomerase II. Both purified recombinant M2- and M3-APC significantly enhanced the activity of topo IIα. Of note, although M3-APC can bind β-catenin, the G2 arrest did not correlate with β-catenin expression or activity, similar to what was seen with M2-APC. More importantly, expression of either M2- or M3-APC also led to increased aneuploidy in cells with full-length endogenous APC but not in cells with truncated endogenous APC that includes the M2-APC region.
Conclusions/Significance
Together, our data establish that the 20-amino acid repeat region of APC interacts with topo IIα to enhance its activity in vitro, and leads to G2 cell cycle accumulation and aneuploidy when expressed in cells containing full-length APC. These findings provide an additional explanation for the aneuploidy associated with many colon cancers that possess truncated APC.
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Citation
Wang, Yang, Coffey, R. J., Osheroff, N., & Neufeld, K. L. (2010). Topoisomerase IIα Binding Domains of Adenomatous Polyposis Coli Influence Cell Cycle Progression and Aneuploidy. PLoS ONE, 5(4). http://dx.doi.org/10.1371/journal.pone.0009994
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Except where otherwise noted, this item's license is described as: ©2010 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.