Up-regulation of the mitotic checkpoint component Mad1 causes chromosomal instability and resistance to microtubule poisons.
The mitotic checkpoint is the major cell cycle checkpoint acting during mitosis to prevent aneuploidy and chromosomal instability, which are hallmarks of tumor cells. Reduced expression of the mitotic checkpoint component Mad1 causes aneuploidy and promotes tumors in mice [Iwanaga Y, et al. (2007) Cancer Res 67:160-166]. However, the prevalence and consequences of Mad1 overexpression are currently unclear. Here we show that Mad1 is frequently overexpressed in human cancers and that Mad1 up-regulation is a marker of poor prognosis. Overexpression of Mad1 causes aneuploidy and chromosomal instability through weakening mitotic checkpoint signaling caused by mislocalization of the Mad1 binding partner Mad2. Cells overexpressing Mad1 are resistant to microtubule poisons, including currently used chemotherapeutic agents. These results suggest that levels of Mad1 must be tightly regulated to prevent aneuploidy and transformation and that Mad1 up-regulation may promote tumors and cause resistance to current therapies.
Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI 53705, USA.
Sean D
SD
Ryan
Eric M C
EM
Britigan
Lauren M
LM
Zasadil
Kristen
K
Witte
Anjon
A
Audhya
Avtar
A
Roopra
Beth A
BA
Weaver
D000782:Aneuploidy; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D043171:Chromosomal Instability / Q000187:drug effects*; D002877:Chromosomes, Human / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D018386:Kinetochores / Q000187:drug effects / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D064246:Mad2 Proteins; D051379:Mice; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D011379:Prognosis; D012097:Repressor Proteins / Q000378:metabolism; D013997:Time Factors; D050257:Tubulin Modulators / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; C501384:MAD1L1 protein, human; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D050257:Tubulin Modulators