MAD2 expression and its significance in mitotic checkpoint control in testicular germ cell tumour

Fung, Maggie K.L.; Cheung, Hiu-wing.; Wong, Hai Ming; Yuen, Hiu‐Fung; Ling, Ming-Tat; Chan, Kowk-Wah; Wong, Yi‐Lee; Cheung, Any; Wang, Xianghong

doi:10.1016/j.bbamcr.2007.03.014

Cited by 24 publications

(18 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In summary, we have shown that down-regulation of MAD2, a feature common to many tumour cell lineages (Takahashi et al, 1999;Wang et al, 2000Wang et al, , 2002Fung et al, 2007) induces cellular senescence in up to a third of the cell population. Due to the fact that paclitaxel targets actively dividing cells, these cells will evade cytotoxic-induced death.…”

Section: Discussionmentioning

confidence: 54%

Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro

et al. 2009

View full text Add to dashboard Cite

BACKGROUND: The mitotic arrest deficiency protein 2 (MAD2) is a key component of the mitotic spindle assembly checkpoint, monitoring accurate chromosomal alignment at the metaphase plate before mitosis. MAD2 also has a function in cellular senescence and in a cell's response to microtubule inhibitory (MI) chemotherapy exemplified by paclitaxel. METHODS: Using an siRNA approach, the impact of MAD2 down-regulation on cellular senescence and paclitaxel responsiveness was investigated. The endpoints of senescence, cell viability, migration, cytokine expression, cell cycle analysis and anaphase bridge scoring were carried out using standard approaches. RESULTS: We show that MAD2 down-regulation induces premature senescence in the MCF7 breast epithelial cancer cell line. These MAD2-depleted (MAD2k) cells are also significantly replicative incompetent but retain viability. Moreover, they show significantly higher levels of anaphase bridges and polyploidy compared to controls. In addition, these cells secrete higher levels of IL-6 and IL-8 representing key components of the senescence-associated secretory phenotype (SASP) with the ability to impact on neighbouring cells. In support of this, MAD2k cells show enhanced migratory ability. At 72 h after paclitaxel, MAD2k cells show a significant further induction of senescence compared with paclitaxel naive controls. In addition, there are significantly more viable cells in the MAD2k MCF7 cell line after paclitaxel reflecting the observed increase in senescence. CONCLUSION: Considering that paclitaxel targets actively dividing cells, these senescent cells will evade cytotoxic kill. In conclusion, compromised MAD2 levels induce a population of senescent cells resistant to paclitaxel.

show abstract

Section: Discussionmentioning

confidence: 54%

Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro

et al. 2009

View full text Add to dashboard Cite

show abstract

“…7,8,15 To confirm the involvement of MTBP in the mitotic checkpoint, we examined the percentage of mitotic cells (mitotic index) following treatment of cells with nocodazole or dimethyl sulfoxide (DMSO; Figure 3c). We measured the mitotic index via flow cytometry using a histone H3 S10P antibody in combination with DNA content analysis.…”

Section: Resultsmentioning

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

“…Disruption of MAD 2 gene expression leads to defects in the mitotic checkpoint, chromosome mis-segregation, and tumorigenesis [6, 10]. In human cancer, there have been only a few reports regarding altered MAD 2 gene expression [10,29,30,31,32,33]. MAD 2 gene is up- or downregulated depending on the tumor type, and both alterations seem to be involved in tumor development.…”

Section: Discussionmentioning

confidence: 99%

Methylation of p16INK4A and Mitotic Arrest Defective Protein 2 (MAD2) Genes in Gastric Marginal-Zone B-Cell Lymphomas

Park

Kim

et al. 2008

Acta Haematol

View full text Add to dashboard Cite

Background: Products of cyclin-dependent kinase inhibitor p16^INK4Aand mitotic arrest defective protein 2 (MAD2) genesare key regulator proteins at the G1 restriction point and mitotic checkpoint of the cell cycle. The objective of this study was to investigate the role of promoter methylation of p16^INK4A and MAD2 genes in gastric marginal-zone B-cell lymphoma (MZBCL). Materials and Methods: Gastric biopsies from 40 patients were analyzed by methylation-specific polymerase chain reaction, and the methylation status was compared with the results of BCL10 expression and t(11;18)(q21;q21) translocation. Results and Conclusion:p16^INK4A was methylated in 30 of 40 MZBCLs (75%). The lymphomas with p16^INK4A methylation tended to be negative for t(11;18)(q21;q21) (p = 0.011). MAD2 gene was methylated in 23 of 38 MZBCLs (61%). Lymphomas with MAD2 gene methylation more frequently expressed BCL10 (p = 0.037). These methylation profiles suggest that p16^INK4A and MAD2 gene may play a role in the pathogenesis of MZBCL via different pathways; MAD2 gene is Helicobacter pylori independent with a close association with BCL10 while p16^INK4A is H. pylori dependent with an inverse correlation with the t(11;18)(q21;q21) translocation.

show abstract

MAD2 expression and its significance in mitotic checkpoint control in testicular germ cell tumour

Cited by 24 publications

References 52 publications

Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro

Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro

MTBP plays a crucial role in mitotic progression and chromosome segregation

Methylation of <i>p</i>16<sup>INK4A</sup> and Mitotic Arrest Defective Protein 2 (<i>MAD</i>2) Genes in Gastric Marginal-Zone B-Cell Lymphomas

Contact Info

Product

Resources

About