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Molecular Cancer Research
Molecular Cancer Research
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Genome Maintenance

p53 Is Not Required for High CIN to Induce Tumor Suppression

Laura C. Funk, Jun Wan, Sean D. Ryan, Charanjeet Kaur, Ruth Sullivan, Avtar Roopra and Beth A. Weaver
Laura C. Funk
1Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin.
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Jun Wan
1Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin.
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Sean D. Ryan
1Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin.
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Charanjeet Kaur
1Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin.
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Ruth Sullivan
2Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin.
3Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
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Avtar Roopra
2Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin.
4Department of Neuroscience, University of Wisconsin-Madison, Madison, Wisconsin.
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Beth A. Weaver
1Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin.
2Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin.
5Department of Oncology/McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin.
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  • For correspondence: baweaver@wisc.edu
DOI: 10.1158/1541-7786.MCR-20-0488 Published January 2021
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Abstract

Chromosomal instability (CIN) is a hallmark of cancer. While low levels of CIN can be tumor promoting, high levels of CIN cause cell death and tumor suppression. The widely used chemotherapeutic, paclitaxel (Taxol), exerts its anticancer effects by increasing CIN above a maximally tolerated threshold. One significant outstanding question is whether the p53 tumor suppressor is required for the cell death and tumor suppression caused by high CIN. Both p53 loss and reduction of the mitotic kinesin, centromere-associated protein-E, cause low CIN. Combining both genetic insults in the same cell leads to high CIN. Here, we test whether high CIN causes cell death and tumor suppression even in the absence p53. Despite a surprising sex-specific difference in tumor spectrum and latency in p53 heterozygous animals, these studies demonstrate that p53 is not required for high CIN to induce tumor suppression. Pharmacologic induction of high CIN results in equivalent levels of cell death due to loss of essential chromosomes in p53+/+ and p53−/− cells, further demonstrating that high CIN elicits cell death independently of p53 function.

Implications: These results provide support for the efficacy of anticancer therapies that induce high CIN, even in tumors that lack functional p53.

This article is featured in Highlights of This Issue, p. 1

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2021;19:112–23

  • Received May 28, 2020.
  • Revision received August 14, 2020.
  • Accepted September 13, 2020.
  • Published first September 18, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 19 (1)
January 2021
Volume 19, Issue 1
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p53 Is Not Required for High CIN to Induce Tumor Suppression
Laura C. Funk, Jun Wan, Sean D. Ryan, Charanjeet Kaur, Ruth Sullivan, Avtar Roopra and Beth A. Weaver
Mol Cancer Res January 1 2021 (19) (1) 112-123; DOI: 10.1158/1541-7786.MCR-20-0488

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p53 Is Not Required for High CIN to Induce Tumor Suppression
Laura C. Funk, Jun Wan, Sean D. Ryan, Charanjeet Kaur, Ruth Sullivan, Avtar Roopra and Beth A. Weaver
Mol Cancer Res January 1 2021 (19) (1) 112-123; DOI: 10.1158/1541-7786.MCR-20-0488
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