Slippage of Mitotic Arrest and Enhanced Tumor Development in Mice with <b>
                     <i>BubR1</i>
                  </b> Haploinsufficiency

Dai, Wei; Wang, Qi; Liu, Tongyi; Swamy, Malisetty V.; Fang, Yuqiang; Xie, Suqing; Mahmood, Radma; Yang, Yang-Ming; Xu, Ming; Rao, Chinthalapally V.

doi:10.1158/0008-5472.can-03-3119

Cited by 282 publications

(277 citation statements)

References 15 publications

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“…Mutations in BubR1 have been detected in colonic cancer (Cahill et al, 1998). Our mouse genetic study shows that haplo-insufficiency of BubR1 results in enhanced genomic instability and development of cancer in lung and colon (Dai et al, 2004;Rao et al, 2005). Consistently, a recent study shows that a compromised BubR1 activity due to specific germline mutations causes aneuploidy, infertility and/or early onset of malignancies (Hanks et al, 2004), strongly suggesting that spindle checkpoint failure is an underlying cause for the development of certain diseases.…”

Section: Introductionsupporting

confidence: 84%

BubR1 is involved in regulation of DNA damage responses

Fang

Wang

et al. 2006

Oncogene

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Section: Introductionsupporting

confidence: 84%

BubR1 is involved in regulation of DNA damage responses

Fang

Wang

et al. 2006

Oncogene

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“…C57BL/6‐based wild‐type (WT), Sgo1 −/+ (Rao et al., 2016; Yamada et al., 2012, 2015, 2016), and BubR1 −/+ (Dai et al., 2004; Rao et al., 2005) mice were bred and maintained in a pathogen‐free rodent barrier facility without treatment for 24–25 months (an observational study). Surviving animals were euthanized and organs were collected following our standard operating procedures (Yamada et al., 2012).…”

Section: Methodsmentioning

confidence: 99%

“…BubR1 −/+ mice showed mitotic slippage in the cells and were colon cancer‐prone (Dai et al., 2004; Rao et al., 2005), and BubR1 H/H hypomorphic mice were identified as a model for premature aging (Baker et al., 2004). Neuronal cell division and axon growth were inhibited by siRNA‐mediated BubR1 knockdown in the mouse brain (Yang et al., 2017).…”

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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“…These results indicate that MVA is a heterogeneous condition and suggest that other mitotic-spindle genes might predispose to human disorders characterized by aneuploidy. Two Bub1b mouse models have recently been described 12,13 . Bub1b -/-mice die in utero.…”

mentioning

confidence: 99%

“…Bub1b -/-mice die in utero. Bub1b +/-mice are developmentally normal but have defective spindle-checkpoint activation and develop lung and colon cancers in response to carcinogen 12 . Bub1b H/H mice, which have B10% normal levels of bubR1, develop aneuploidy, cataracts and growth retardation, which are characteristic of MVA, but do not have an increased cancer incidence.…”

mentioning

confidence: 99%