Enhanced genomic instabilities caused by deregulated microtubule dynamics and chromosome segregation: a perspective from genetic studies in mice

Rao, Chinthalapally V.; Yamada, Hiroshi; Yao, Yixin; Dai, Wei

doi:10.1093/carcin/bgp081

Cited by 97 publications

(80 citation statements)

References 61 publications

(92 reference statements)

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“…Insufficient mitotic arrest results in abnormal cell cycle progression and decreased cell proliferation via chromosome abnormality. 12,[17][18][19] Hence, we wanted to examine the long-term consequences of MTBP downmodulation on cellular behavior and chromosome aneuploidy. We first examined the effect of MTBP downmodulation on cell growth using colony outgrowth assays (Figure 4a).…”

Section: Resultsmentioning

confidence: 99%

“…Both decreased and increased levels of mitotic checkpoint proteins cause a similar cellular response, including improper mitotic progression, chromosome aneuploidy, senescence, and tumor development via impaired and overactive mitotic checkpoint activities, respectively. 12,18,22,23 Therefore, proteins involved in the mitotic checkpoint cannot be simply categorized as either oncogenes or tumor suppressors. Mice null for Mad1, Mad2, BubR1, Bub1, and Bub3 show early embryonic lethal phenotypes because of chromosome missegregation.…”

Section: Discussionmentioning

confidence: 99%

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MTBP plays a crucial role in mitotic progression and chromosome segregation

et al. 2011

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Murine double minute 2 (MDM2) binding protein (MTBP) has been implicated in tumor cell proliferation, but the underlying mechanisms remain unclear. The results of MTBP expression analysis during cell cycle progression demonstrated that MTBP protein was rapidly degraded during mitosis. Immunofluorescence studies revealed that a portion of MTBP was localized at the kinetochores during prometaphase. MTBP overexpression delayed mitotic progression from nuclear envelope breakdown (NEB) to anaphase onset and induced abnormal chromosome segregation such as lagging chromosomes, chromosome bridges, and multipolar chromosome segregation. Conversely, MTBP downmodulation caused an abbreviated metaphase and insufficient mitotic arrest, resulting in abnormal chromosome segregation, aneuploidy, decreased cell proliferation, senescence, and cell death, similar to that of Mad2 (mitotic arrest-deficient 2) downmodulation. Furthermore, MTBP downmodulation inhibited the accumulation of Mad1 and Mad2, but not BubR1 (budding uninhibited by benzimidazoles related 1), on the kinetochores, whereas MTBP overexpression inhibited the release of Mad2 from the metaphase kinetochores. These results may imply that MTBP has an important role in recruiting and/or retaining the Mad1/Mad2 complex at the kinetochores during prometaphase, but its degradation is required for silencing the mitotic checkpoint. Together, this study indicates that MTBP has a crucial role in proper mitotic progression and faithful chromosome segregation, providing new insights into regulation of the mitotic checkpoint. Cell Death and Differentiation (2011) 18, 1208-1219; doi:10.1038/cdd.2010.189; published online 28 January 2011Murine double minute 2 (MDM2) binding protein (MTBP) was originally identified as a protein that interacts with the oncoprotein MDM2, a major negative regulator of the tumor suppressor p53. 1 Overexpression of MTBP was shown to suppress cell proliferation and colony formation of several human cancer cell lines independent of their p53 status. 1 Brady et al. 2 reported that overexpression of MTBP in MCF7 cells resulted in MDM2 stabilization and subsequent p53 degradation. However, our previous findings demonstrated that complete deletion of MTBP in mice resulted in an early embryonic lethal phenotype independent of p53. 3 Furthermore, MTBP heterozygous mice (MTBP þ /À ) were neither tumor prone nor did they show any obvious phenotypes. Nonetheless, Mtbp þ /À p53 þ /À mice showed an increased frequency of metastatic tumors compared with p53 þ /À mice, suggesting the possible involvement of MTBP in tumor progression. 3 Recently, Odvody et al. 4 reported that a reduced MTBP level delayed Myc-induced lymphomagenesis independent of Mdm2 and p53. Thus, a vast majority of the results support the p53-independent functions of MTBP and its involvement in cell proliferation and tumor progression.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MTBP plays a crucial role in mitotic progression and chromosome segregation

et al. 2011

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“…To investigate the effects of genomic instability and resulting aneuploidy on carcinogenesis, various mouse models have been developed, mainly by targeting mitotic or other cell cycle regulators (Foijer, Draviam, & Sorger, 2008; Rao, Yamada, Yao, & Dai, 2009; Ricke, van Ree, & van Deursen, 2008; Schvartzman, Sotillo, & Benezra, 2010). Shugoshin‐1 (Sgo1) protects cohesin proteins and centrosome integrity (Salic, Waters, & Mitchison, 2004; Schöckel, Möckel, Mayer, Boos, & Stemmann, 2011).…”

Section: Introductionmentioning

confidence: 99%

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

et al. 2018

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SummarySpontaneous late‐onset Alzheimer's disease (LOAD) accounts for more than 95% of all human AD. As mice do not normally develop AD and as understanding on molecular processes leading to spontaneous LOAD has been insufficient to successfully model LOAD in mouse, no mouse model for LOAD has been available. Existing mouse AD models are all early‐onset AD (EOAD) models that rely on forcible expression of AD‐associated protein(s), which may not recapitulate prerequisites for spontaneous LOAD. This limitation in AD modeling may contribute to the high failure rate of AD drugs in clinical trials. In this study, we hypothesized that genomic instability facilitates development of LOAD and tested two genomic instability mice models in the brain pathology at the old age. Shugoshin‐1 (Sgo1) haploinsufficient (∓) mice, a model of chromosome instability (CIN) with chromosomal and centrosomal cohesinopathy, spontaneously exhibited a major feature of AD pathology; amyloid beta accumulation that colocalized with phosphorylated Tau, beta‐secretase 1 (BACE), and mitotic marker phospho‐Histone H3 (p‐H3) in the brain. Another CIN model, spindle checkpoint‐defective BubR1−/+ haploinsufficient mice, did not exhibit the pathology at the same age, suggesting the prolonged mitosis‐origin of the AD pathology. RNA‐seq identified ten differentially expressed genes, among which seven genes have indicated association with AD pathology or neuronal functions (e.g., ARC, EBF3). Thus, the model represents a novel model that recapitulates spontaneous LOAD pathology in mouse. The Sgo1−/+ mouse may serve as a novel tool for investigating mechanisms of spontaneous progression of LOAD pathology, for early diagnosis markers, and for drug development.

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“…Previous studies have revealed that TRIP13 is a novel component of the spindle assembly checkpoint (SAC) pathway (14)(15)(16)(17), which is crucial for the accurate distribution of duplicated chromosomes (18). Defects in the SAC pathway induce failure in chromosome separation and result in aneuploidy, which eventually leads to cellular apoptosis or transformation (19). TRIP13 was also reported to promote nonhomologous end-joining, and its overexpression resulted in cellular transformation and resistance to chemotherapeutic agents, indicating that aberrant expression of TRIP13 may be associated with tumor progression (20).…”

Section: Introductionmentioning

confidence: 99%

TRIP13 is expressed in colorectal cancer and promotes cancer cell invasion

et al. 2016

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Abstract. Thyroid hormone receptor interactor 13 (TRIP13) is a member of the ATPases associated with various cellular activities family of proteins and is highly conserved in a wide range of species. Recent studies have demonstrated that TRIP13 is critical for the inactivation of the spindle assembly checkpoint and is associated with the progression of certain cancers. In the present study, the role of TRIP13 in colorectal cancer (CRC) was examined. Reverse transcription-quantitative polymerase chain reaction analysis revealed that TRIP13 messenger RNA was highly expressed in multiple CRC tissues. The depletion of TRIP13 in CRC cells suppressed cell proliferation, migration and invasion. To determine whether the catalytic activity of TRIP13 was critical for cancer progression, an inactive mutant of TRIP13 was expressed in CRC cells. The invasion of cancer cells that expressed the mutant TRIP13 was significantly reduced compared with that of the wild type TRIP13-expressing cancer cells. These results indicate that TRIP13 could be a potential target for CRC treatment. IntroductionThe ATPases associated with various cellular activities (AAA+) family of proteins comprises a functionally different group of enzymes that are involved in an array of cellular processes, including protein degradation, protein-complex disassembly and DNA replication (1). The AAA+ proteins are present in all kingdoms, and are characterized by the presence of conserved AAA+ domains that contain Walker A and Walker B motifs, followed by a conserved region called second region of homology (2). The majority of AAA+ proteins form hexamers to exert their biological functions. The chemical energy generated by adenosine triphosphate (ATP) hydrolysis by this family of proteins induces conformational changes in the substrate proteins to modulate their functions (3,4).A previous study reported that certain AAA+ enzymes are associated with tumor progression (5). For example, reptin [also known as RuvB-like (RUVBL) 2] and pontin (RUVBL1) have been demonstrated to be overexpressed in several tumors (5). These proteins interact with c-Myc or β-catenin, thus modulating their transcriptional activities to promote tumor progression (6). AAA+ proteins hydrolyze ATP, and thus, chemical inhibitors that disrupt the activities of cancer-associated AAA+ proteins may represent promising anti-cancer drugs.Thyroid hormone receptor interactor 13 (TRIP13, also known as 16E1BP and pachytene checkpoint 2) is a member of the AAA+ family proteins and is conserved in a wide range of species (7). It was first identified as a protein that interacts with human papilloma virus E1 proteins by a yeast two-hybrid analysis, but the physiological function of the interaction remains unknown (7). Accumulating studies have demonstrated that TRIP13 plays pivotal roles in meiotic recombination and DNA repair in plants, yeast, worms and mice (8-12). TRIP13 forms a stable hexameric ring, and ATP binding, as well as ATP hydrolysis, are critical for the function of the protein (13). Previous...

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Enhanced genomic instabilities caused by deregulated microtubule dynamics and chromosome segregation: a perspective from genetic studies in mice

Cited by 97 publications

References 61 publications

MTBP plays a crucial role in mitotic progression and chromosome segregation

MTBP plays a crucial role in mitotic progression and chromosome segregation

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

TRIP13 is expressed in colorectal cancer and promotes cancer cell invasion

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