Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis

Jeganathan, Karthik B.; Malureanu, Liviu; Baker, Darren J.; Abraham, Susan C.; Deursen, Jan M. van

doi:10.1083/jcb.200706015

Cited by 205 publications

(300 citation statements)

References 56 publications

(98 reference statements)

Supporting

Mentioning

281

Contrasting

Unclassified

Order By: Relevance

“…Coincident with downregulation of PLK1, several members involved in the mitotic checkpoint function remained also down-regulated in treated cells. Partial loss of checkpoint control by such genes has often been associated to abnormal mitosis (Jeganathan et al 2007). Among the down-regulated mitotic checkpoint gene members detected in this work, it is noteworthy the down-regulation of HEC1 gene.…”

Section: Discussionmentioning

confidence: 99%

Effect of rosemary polyphenols on human colon cancer cells: transcriptomic profiling and functional enrichment analysis

et al. 2012

View full text Add to dashboard Cite

In this work, the effect of rosemary extracts rich on polyphenols obtained using pressurized fluids was investigated on the gene expression of human SW480 and HT29 colon cancer cells. The application of transcriptomic profiling and functional enrichment analysis was done via two computational approaches, Ingenuity Pathway Analysis and Gene Set Enrichment Analysis. These two approaches were used for functional enrichment analysis as a previous step for a reliable interpretation of the data obtained from microarray analysis. Reverse transcription quantitative-PCR was used to confirm relative changes in mRNA levels of selected genes from microarrays. The selection of genes was based on their expression change, adjusted p value, and known biological function. According to genome-wide transcriptomics analysis, rosemary polyphenols altered the expression of *4 % of the genes covered by the Affymetrix Human Gene 1.0ST chip in both colon cancer cells. However, only *18 % of the differentially expressed genes were common to both cell lines, indicating markedly different expression profiles in response to the treatment. Differences in induction of G2/ M arrest observed by rosemary polyphenols in the two colon adenocarcinoma cell lines suggest that the extract may be differentially effective against tumors with specific mutational pattern. From our results, it is also concluded that rosemary polyphenols induced a low degree of apoptosis indicating that other multiple signaling pathways may contribute to colon cancer cell death.

show abstract

Section: Discussionmentioning

confidence: 99%

Effect of rosemary polyphenols on human colon cancer cells: transcriptomic profiling and functional enrichment analysis

et al. 2012

View full text Add to dashboard Cite

show abstract

“…We first examined MEFs with graded reduction in Bub1 expression (14). Western blot analysis demonstrated that levels of Ser18-phosphorylated p53 and p21 were indeed elevated in Bub1 H/H and Bub1 H/− MEFs, but not in wildtype or Bub1 +/H or Bub1 +/− cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cdc20 AAA mice were described previously (19) and were crossed with p53 knockout mice (a generous gift from L. Donehower at Baylor College of Medicine, Houston) to produce double-mutant mice. Bub1-deficient mice were generated previously (14). Atm-deficient mice were originally generated by Barlow et al (30) and were obtained from C. Zhu at MD Anderson Cancer Center, Houston.…”

Section: Methodsmentioning

confidence: 99%

“…Genetic analyses in budding yeasts unequivocally demonstrated that the spindle assembly checkpoint was essential in maintaining chromosomal stability (9,10). Studies of engineered mouse strains carrying mutations in SAC components also indicated the importance of the checkpoint in maintaining chromosome stability (11)(12)(13)(14)(15)(16)(17)(18)(19), and BUBR1 was found mutated in a rare human disorder, mosaic variegated aneuploidy (20).…”

mentioning

confidence: 99%

See 1 more Smart Citation

The ATM–p53 pathway suppresses aneuploidy-induced tumorigenesis

Li¹,

Xiao²,

Baker

et al. 2010

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

Self Cite

219

247

View full text Add to dashboard Cite

The spindle assembly checkpoint (SAC) is essential for proper sister chromatid segregation. Defects in this checkpoint can lead to chromosome missegregation and aneuploidy. An increasing body of evidence suggests that aneuploidy can play a causal role in tumorigenesis. However, mutant mice that are prone to aneuploidy have only mild tumor phenotypes, suggesting that there are limiting factors in the aneuploidy-induced tumorigenesis. Here we provide evidence that p53 is such a limiting factor. We show that aneuploidy activates p53 and that loss of p53 drastically accelerates tumor development in two independent aneuploidy models. The p53 activation depends on the ataxia-telangiectasia mutated (ATM) gene product and increased levels of reactive oxygen species. Thus, the ATM-p53 pathway safeguards not only DNA damage but also aneuploidy.

show abstract

“…[23][24][25][26][27][28] However, mice heterozygous for Mad1 and Mad2 or mice with the hypomorphic alleles of BubR1 (BubR1 H ), Bub3 (Bub3 H ), and Bub1 (Bub1 H ) develop either late onset of spontaneous tumors or early aging-associated phenotypes, whereas heterozygous mice for Bub1, Bub3, and BubR1 show no obvious phenotypes. 23,27,[29][30][31] Importantly, mice overexpressing Mad2 also show accelerated tumorigenesis with chromosomal instability. 11,12 These results suggest that a threshold level of the mitotic checkpoint-related proteins is necessary for preventing cells from chromosome missegregation, tumor development, and aging-associated phenotypes.…”

Section: Discussionmentioning

confidence: 99%

MTBP plays a crucial role in mitotic progression and chromosome segregation

et al. 2011

View full text Add to dashboard Cite

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.

show abstract

Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis

Cited by 205 publications

References 56 publications

Effect of rosemary polyphenols on human colon cancer cells: transcriptomic profiling and functional enrichment analysis

Effect of rosemary polyphenols on human colon cancer cells: transcriptomic profiling and functional enrichment analysis

The ATM–p53 pathway suppresses aneuploidy-induced tumorigenesis

MTBP plays a crucial role in mitotic progression and chromosome segregation

Contact Info

Product

Resources

About