2021
DOI: 10.1158/1541-7786.mcr-20-0488
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p53 Is Not Required for High CIN to Induce Tumor Suppression

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-ass… Show more

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Cited by 16 publications
(11 citation statements)
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“…However, not every tumor carries loss-of-function p53 mutations (Soussi and Wiman 2007 ), suggesting the existence of alternative pathways that restrain CIN perpetuation in tissues. This idea is further supported by studies in transgenic mice demonstrating that high CIN induces comparable apoptosis and tumor suppression levels in p53 null and p53 wild-type animals (Funk et al 2021 ). Similarly, another study reported that loss-of-function mutations in the BCL9L gene, particularly in aneuploid colorectal cancer cells, promote their propagation by reducing caspase-2 and attenuating cell death, irrespective of p53 status, after chromosome segregation errors (López-García et al 2017 ).…”
Section: Mechanisms Of Cin Attenuation In Cancermentioning
confidence: 79%
“…However, not every tumor carries loss-of-function p53 mutations (Soussi and Wiman 2007 ), suggesting the existence of alternative pathways that restrain CIN perpetuation in tissues. This idea is further supported by studies in transgenic mice demonstrating that high CIN induces comparable apoptosis and tumor suppression levels in p53 null and p53 wild-type animals (Funk et al 2021 ). Similarly, another study reported that loss-of-function mutations in the BCL9L gene, particularly in aneuploid colorectal cancer cells, promote their propagation by reducing caspase-2 and attenuating cell death, irrespective of p53 status, after chromosome segregation errors (López-García et al 2017 ).…”
Section: Mechanisms Of Cin Attenuation In Cancermentioning
confidence: 79%
“…Aneuploidy is a common characteristic of tumor cells and CIN is one of the hallmarks of cancer. However, in cultured cells including MEFs both aneuploidy and CIN often cause a proliferative disadvantage (Kops et al 2004; Weaver et al 2007; Funk et al 2021). Accordingly, while low levels of aneuploidy and/or CIN, induced by interference with mitotic checkpoint proteins, are weakly tumor promoting in mice, high levels cause cell death and tumor suppression, and are associated with senescence and aging (Weaver et al 2007; Lopez-Otin et al 2013; Silk et al 2013; Santaguida et al 2017).…”
Section: Discussionmentioning
confidence: 99%
“…Accordingly, while low levels of aneuploidy and/or CIN, induced by interference with mitotic checkpoint proteins, are weakly tumor promoting in mice, high levels cause cell death and tumor suppression, and are associated with senescence and aging (Weaver et al 2007; Lopez-Otin et al 2013; Silk et al 2013; Santaguida et al 2017). Cell death induced by high CIN levels can occur through activation of p53, but p53 is not required for high CIN to suppress tumor formation (Kops et al 2004; Thompson and Compton 2010; Santaguida et al 2017; Funk et al 2021). Complicating the interpretation of these findings, most proteins that function in mitosis and the mitotic checkpoint have additional, interphase roles outside of chromosome segregation, which often occur in pathways that are likely to influence tumor phenotypes.…”
Section: Discussionmentioning
confidence: 99%
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“…Low rates of CIN can be tumor-promoting through the gain of oncogenes or loss of tumor suppressors ( 9 13 ). Higher rates of CIN cause cell death, likely through loss of essential chromosomes, and tumor suppression ( 14 22 ). A preexisting rate of CIN can sensitize cells to another CIN-inducing insult, and cells with CIN are more sensitive to paclitaxel, which causes CIN due to multipolar spindles in patient tumors and at clinically relevant doses in cell culture ( 23 28 ).…”
mentioning
confidence: 99%