Loss of BubR1 acetylation causes defects in spindle assembly checkpoint signaling and promotes tumor formation

Park, Inai; Lee, Hae‐Ock; Choi, Eunhee; Lee, Yoo-Kyung; Kwon, Mi‐Sun; Min, Jaewon; Park, Pil-Gu; Lee, Seonju; Kong, Young‐Yun; Gong, Gyungyub; Lee, Hyun‐Sook

doi:10.1083/jcb.201210099

Cited by 48 publications

(79 citation statements)

References 49 publications

(94 reference statements)

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“…Lysine (K) 250 and 688 on BubR1 have been identified as the potential deacetylation targets of Sirt2 in human cells (North et al., 2014; Suematsu et al., 2014), which are corresponding to K243 and K657 residues in mice (Park et al., 2013). …”

Section: Resultsmentioning

confidence: 99%

“…Chromosome segregation in cells expressing BubR1‐K250Q was delayed, whereas mitotic progression was accelerated in cells expressing BubR1‐K250R (Choi et al., 2009). Loss of BubR1 acetylation causes defects in SAC signaling and promotes tumor formation in mice (Park et al., 2013). Recently, North et al.…”

Section: Discussionmentioning

confidence: 99%

“…In specific, Sirt2 was shown to be able to modulate BubR1 stability in vitro and in vivo through deacetylation (North et al., 2014; Suematsu et al., 2014). Moreover, numerous studies demonstrated that deacetylation status of BubR1 is essential for maintaining the mitotic structure integrity and the control of cell cycle (Choi et al., 2009; Park et al., 2013; Suematsu et al., 2014). …”

Section: Introductionmentioning

confidence: 99%

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Sirt2‐BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality

et al. 2017

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SummaryThe level of Sirt2 protein is reduced in oocytes from aged mice, while exogenous expression of Sirt2 could ameliorate the maternal age‐associated meiotic defects. To date, the underlying mechanism remains unclear. Here, we confirmed that specific depletion of Sirt2 disrupts maturational progression and spindle/chromosome organization in mouse oocytes, with compromised kinetochore–microtubule attachments. Candidate screening revealed that acetylation state of lysine 243 on BubR1 (BubR1‐K243, an integral part of the spindle assembly checkpoint complex) functions during oocyte meiosis, and acetylation‐mimetic mutant BubR1‐K243Q results in the very similar phenotypes as Sirt2‐knockdown oocytes. Furthermore, we found that nonacetylatable‐mimetic mutant BubR1‐K243R partly prevents the meiotic deficits in oocytes depleted of Sirt2. Importantly, BubR1‐K243R overexpression in oocytes derived from aged mice markedly suppresses spindle/chromosome anomalies and thereupon lowers the incidence of aneuploid eggs. In sum, our data suggest that Sirt2‐dependent BubR1 deacetylation involves in the regulation of meiotic apparatus in normal oocytes and mediates the effects of advanced maternal age on oocyte quality.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sirt2‐BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality

et al. 2017

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“…These data provide substantial evidence that the acetylation status of survivin is critical for genomic stability during mitosis. However, we are mindful that acetylation of other mitotic proteins including aurora-B 25 and BubR1 itself, 23 as well as certain cytokinetic proteins, may contribute to and exacerbate the mitotic and cytokinetic abnormalities seen in the chemically-induced acetylated state. In addition to mitotic defects we found that mimicking acetylation of survivin leads to some relocation to the nucleus, which concurs with Wang et al, (2010b).…”

Section: Discussionmentioning

confidence: 99%

“…For example, depletion of the ubiquitous and highly conserved HDAC3 prevents proper construction of the mitotic spindle and weakens kinetochore-microtubule attachment in prometaphase cells. 22 Furthermore many mitotic proteins, including tubulin, BubR1, 23 APC, shuogoshin-2, 24 CPPs aurora-B kinase 25 and survivin 6 are acetylated. Using acetylation mimetics, Wang et al, (2010) demonstrated that survivin acetylation at K129 influences its subcellular localization in interphase cells.…”

Section: Discussionmentioning

confidence: 99%

Mitotic activity of survivin is regulated by acetylation at K129

2015

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Survivin is a cancer-associated protein regulated by multiple factors, including acetylation at K129 within its C-terminal a-helical tail. Acetylation of survivin is being pursued as a potential prognostic marker in breast cancer. This modification at K129 may cause nuclear accumulation of survivin in interphase cells; however, whether this affects its essential role during mitosis has not been addressed. We posited whether mimicking acetylation of survivin at K129 alters its activity during mitosis. Fluorescence microscopy and time-lapse imaging showed that, mutating this site to an alanine to act as a constitutive acetyl mimetic, K129A, causes defects in chromosome segregation and cytokinesis. As a non-acetylatable version, K129R, also has difficulty during mitotic exit, we conclude that cyclical acetylation and deacetylation is required for fully functional survivin during mitosis.

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BUB1B promotes hepatocellular carcinoma progression via activation of the mTORC1 signaling pathway

et al. 2020

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Background and Aims Accumulating studies identified that BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) is integrally involved in the initiation and development of tumors. Nevertheless, the precise biological role and underlying mechanisms of BUB1B in hepatocellular carcinoma (HCC) remain indistinct. Method To figure out the role of BUB1B in HCC, we first assessed its expression using The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases. We then verified BUB1B expression in HCC tissues, nontumor tissues, and HCC cell lines through western blotting, quantitative reverse transcription‐polymerase chain reaction, and immunohistochemistry. To explore the specific function of BUB1B in HCC in vivo and in vitro, we performed the flow cytometry, Cell Counting Kit‐8, 5‐ethynyl‐2′‐deoxyuridine incorporation, colony formation, Transwell, wound‐healing, subcutaneous tumor growth, and metastasis assays. Additionally, we identified the BUB1B‐regulated pathways involved in HCC by using gene set enrichment analysis. Results Our data displayed that higher BUB1B expression was detected in HCC tissues and HCC cell lines. The overexpression of BUB1B was positively correlated with adverse clinicopathological characteristics. Survival analyses showed that lower recurrence‐free and overall survival rates were correlated with the overexpression of BUB1B in patients with HCC. Moreover, the malignancy of HCC was facilitated by BUB1B both in vivo and in vitro. Lastly, the results were confirmed by western blots, which showed that BUB1B upregulated mTORC1 signaling pathway in HCC. Meanwhile, the oncogenic effect of BUB1B will be impaired when the mTORC1 signaling pathway was inhibited by rapamycin. Conclusion We highlighted that BUB1B played an oncogenic role in HCC and was identified as a possible clinical prognostic factor and a potential novel therapeutic target for HCC.

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Loss of BubR1 acetylation causes defects in spindle assembly checkpoint signaling and promotes tumor formation

Abstract: Failure of chromosome–spindle attachment and a weakened spindle assembly checkpoint lead to genetic instability and cancer in mice expressing acetylation-deficient BubR1.

Cited by 48 publications

References 49 publications

Sirt2‐BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality

Sirt2‐BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality

Mitotic activity of survivin is regulated by acetylation at K129

BUB1B promotes hepatocellular carcinoma progression via activation of the mTORC1 signaling pathway

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