p53 Is Not Required for High CIN to Induce Tumor Suppression

Funk, Laura C.; Wan, Jun; Ryan, Sean D.; Kaur, Charanjeet; Sullivan, Ruth; Roopra, Avtar; Weaver, Beth A.

doi:10.1158/1541-7786.mcr-20-0488

Cited by 15 publications

(11 citation statements)

References 98 publications

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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%

Mechanisms of chromosomal instability (CIN) tolerance in aggressive tumors: surviving the genomic chaos

Dhital

Rodríguez-Bravo

2023

Chromosome Res

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Chromosomal instability (CIN) is a pervasive feature of human cancers involved in tumor initiation and progression and which is found elevated in metastatic stages. CIN can provide survival and adaptation advantages to human cancers. However, too much of a good thing may come at a high cost for tumor cells as excessive degree of CIN-induced chromosomal aberrations can be detrimental for cancer cell survival and proliferation. Thus, aggressive tumors adapt to cope with ongoing CIN and most likely develop unique susceptibilities that can be their Achilles’ heel. Determining the differences between the tumor-promoting and tumor-suppressing effects of CIN at the molecular level has become one of the most exciting and challenging aspects in cancer biology. In this review, we summarized the state of knowledge regarding the mechanisms reported to contribute to the adaptation and perpetuation of aggressive tumor cells carrying CIN. The use of genomics, molecular biology, and imaging techniques is significantly enhancing the understanding of the intricate mechanisms involved in the generation of and adaptation to CIN in experimental models and patients, which were not possible to observe decades ago. The current and future research opportunities provided by these advanced techniques will facilitate the repositioning of CIN exploitation as a feasible therapeutic opportunity and valuable biomarker for several types of human cancers.

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Section: Mechanisms Of Cin Attenuation In Cancermentioning

confidence: 79%

Mechanisms of chromosomal instability (CIN) tolerance in aggressive tumors: surviving the genomic chaos

Dhital

Rodríguez-Bravo

2023

Chromosome Res

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“…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%

“…Supernumerary centrosomes are believed to contribute to tumor formation via induction of chromosome missegregation and chromosomal instability (CIN). Whereas low CIN rates can be advantageous to tumor cells and support tumor formation and progression, high rates of CIN cause cell death and tumor suppression (Kops et al 2004; Weaver et al 2007; Funk et al 2021). Accordingly, high-level centrosome amplification can cause cell death as a consequence of multipolar mitotic divisions in vitro and in vivo , especially in cells with inefficient centrosome clustering mechanisms (Ganem et al 2009; Silkworth et al 2009; Marthiens et al 2013; Sercin et al 2016).…”

Section: Introductionmentioning

confidence: 99%

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STIL overexpression shortens lifespan and reduces tumor formation in mice

Moussa,

Cosenza,

Wohlfromm

et al. 2023

Preprint

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Centrosomes are the major microtubule organizing centers of animal cells. Supernumerary centrosomes are a common feature of human tumors and associated with karyotype abnormalities and aggressive disease, but whether they are cause or consequence of cancer remains controversial. Here, we analyzed the consequences of centrosome amplification by generating transgenic mice in which centrosome numbers can be increased by overexpression of the structural centrosome protein STIL. We show that STIL overexpression induces centrosome amplification and aneuploidy, leading to senescence, apoptosis, and impaired proliferation in mouse embryonic fibroblasts, and microcephaly with increased perinatal lethality and shortened lifespan in mice. Importantly, both overall tumor formation in mice with constitutive, global STIL overexpression and chemical skin carcinogenesis in animals with inducible, skin-specific STIL overexpression were reduced, an effect that was not rescued by concomitant p53 inactivation. These results suggest that supernumerary centrosomes impair proliferationin vitroas well asin vivo, resulting in reduced lifespan and spontaneous as well as carcinogen-induced tumor formation.

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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%

HPV16 E6 induces chromosomal instability due to polar chromosomes caused by E6AP-dependent degradation of the mitotic kinesin CENP-E

Cosper

Hrycyniak

Paracha

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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Chromosome segregation during mitosis is highly regulated to ensure production of genetically identical progeny. Recurrent mitotic errors cause chromosomal instability (CIN), a hallmark of tumors. The E6 and E7 oncoproteins of high-risk human papillomavirus (HPV), which causes cervical, anal, and head and neck cancers (HNC), cause mitotic defects consistent with CIN in models of anogenital cancers, but this has not been studied in the context of HNC. Here, we show that HPV16 induces a specific type of CIN in patient HNC tumors, patient-derived xenografts, and cell lines, which is due to defects in chromosome congression. These defects are specifically induced by the HPV16 oncogene E6 rather than E7. We show that HPV16 E6 expression causes degradation of the mitotic kinesin CENP-E, whose depletion produces chromosomes that are chronically misaligned near spindle poles (polar chromosomes) and fail to congress. Though the canonical oncogenic role of E6 is the degradation of the tumor suppressor p53, CENP-E degradation and polar chromosomes occur independently of p53. Instead, E6 directs CENP-E degradation in a proteasome-dependent manner via the E6-associated ubiquitin protein ligase E6AP/UBE3A. This study reveals a mechanism by which HPV induces CIN, which may impact HPV-mediated tumor initiation, progression, and therapeutic response.

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p53 Is Not Required for High CIN to Induce Tumor Suppression

Cited by 15 publications

References 98 publications

Mechanisms of chromosomal instability (CIN) tolerance in aggressive tumors: surviving the genomic chaos

Mechanisms of chromosomal instability (CIN) tolerance in aggressive tumors: surviving the genomic chaos

STIL overexpression shortens lifespan and reduces tumor formation in mice

HPV16 E6 induces chromosomal instability due to polar chromosomes caused by E6AP-dependent degradation of the mitotic kinesin CENP-E

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