Significance of MAD2 expression to mitotic checkpoint control in ovarian cancer cells.
Chromosome instability is a commonly observed feature in ovarian carcinoma. Mitotic checkpoint controls are thought to be essential for accurate chromosomal segregation, and MAD2 is a key component of this checkpoint. In this study, we investigated the competence of the mitotic checkpoint and its relationship to the expression of MAD2 protein in seven ovarian cancer cell lines. We found that a significant number (43%, three of seven cell lines) of the tested ovarian cancer cells failed to arrest in the G(2)-M phase of the cell cycle in response to microtubule disruption. This loss of mitotic checkpoint control was associated with reduced expression of the MAD2 protein. To additionally understand the significance of the MAD2 to mitotic checkpoint control, we established an inducible expression system in which MAD2 was induced by the addition of ponasterone A. Notably, the induced expression of MAD2 in two checkpoint-defective ovarian cancer cell lines led to the restoration of mitotic checkpoint response to spindle-disrupting agents. Taken together, our findings suggest that the steady-state amount of MAD2 inside cells may represent a molecular switch for mitotic checkpoint control. This provides a novel insight into the molecular basis of CIN in ovarian carcinoma and has implications for effective use of checkpoint-targeting drugs.
Wang
Xianghong
X
Department of Anatomy, Faculty of Medicine, University of Hong Kong, Hong Kong.
Jin
Dong-Yan
DY
Ng
Raymond W M
RW
Feng
Huichen
H
Wong
Yong C
YC
Cheung
Annie L M
AL
Tsao
Sai W
SW
D002135:Calcium-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D005260:Female; D006801:Humans; D064246:Mad2 Proteins; D008938:Mitosis / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010957:Plasmids / Q000235:genetics; D012097:Repressor Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured
D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D012097:Repressor Proteins