APC mutations lead to cytokinetic failures in vitro and tetraploid genotypes in Min mice
Open accessAbstract
Previous research has proposed that genomic instability contributes to cancer progression, with its initiation linked to tetraploid cell formation (Duesberg, P., and R. Li. 2003. Cell Cycle. 2:202–210; Ganem, N.J., Z. Storchova, and D. Pellman. 2007. Curr. Opin. Genet. Dev. 17:157–162). However, there is little direct evidence linking cancer-causing mutations with such events, and it remains controversial whether genomic instability is a cause or an effect of cancer. In this study, we show that adenomatous polyposis coli (APC) mutations found in human colorectal cancers dominantly inhibit cytokinesis by preventing mitotic spindle anchoring at the anaphase cortex and, thus, blocking initiation of the cytokinetic furrow. We find that dividing crypt cells in the small intestines of APCMin/+ mice exhibit similar mitotic defects, including misoriented spindles and misaligned chromosomes. These defects are observed in normal crypt cells with wild-type levels of β-catenin and, importantly, are associated with tetraploid genotypes. We provide direct evidence that the dominant activity of APC mutants induces aneuploidy in vivo. Our data support a model whereby tetraploid cells represent a first step in the onset of genomic instability and colorectal cancer.
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Changes in APC dosage can affect cellular motility, migration and polarity.
“Several studies have previously shown that changes in APC dosage can affect cellular motility, migration and polarity [24, 38, 39], and can induce the development of early intestinal neoplasms [40].”
From Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells (2018) · cites this paper as [24]
The Discussion (page unavailable) says that APC-mutant changes in microtubule behavior can alter cell polarity, and the Results report misoriented mitotic spindles in Min mice. The paper does not report an effect on cellular motility or migration; the evidence concerns APC mutations and mutant expression rather than APC dosage specifically. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAPC has been implicated in the regulation of chromosomal segregation and the formation of the mitotic spindle, with APC mutations causing chromosomal abnormalities.
“As APC has also been implicated in the regulation of chromosomal segregation and the formation of the mitotic spindle, with APC mutations causing chromosomal abnormalities [24]”
From Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells (2018) · cites this paper as [24]
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- Authors
- Caldwell, C. M., Green, R. A., & Kaplan, K. B.
- Affiliations
- University of California, Davis (US)
- Venue
- The Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2007-09-24
- Volume
- 178
- Issue
- 7
- Pages
- 1109-1120
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2064647
- OpenAlex
- W2154083988
- Cited by
- 164
- References
- 38
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 4 · 2022: 7 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 6 · 2017: 9 · 2016: 10 · 2015: 10 · 2014: 8 · 2013: 13 · 2012: 13
- FWCI
- 7.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Cell Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- APC mutation, colorectal cancer, cytokinesis, tetraploidy, genomic instability, furrow formation, aneuploidy, ApcMin/+ mice, crypt cells, β-catenin, chromosome misalignment
- MeSH terms
- Animals, Cell Line, Cell Nucleus, Genotype, Humans, Intestine, Small, Mice, Mutant Strains, Mitosis, Spindle Apparatus, Models, Biological, Mutation, Polyploidy, Adenomatous Polyposis Coli, Cytokinesis, Mutant Proteins, Mice, Organelle Size
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