Complete loss of the tumor suppressor MAD2 causes premature cyclin B degradation and mitotic failure in human somatic cells Journal Article

Authors: Michel, L.; Diaz-Rodriguez, E.; Narayan, G.; Hernando, E.; Murty, V. V. V. S.; Benezra, R.
Article Title: Complete loss of the tumor suppressor MAD2 causes premature cyclin B degradation and mitotic failure in human somatic cells
Abstract: MAD2 inhibits the anaphase-promoting complex when chromosomes are unattached to the mitotic spindle. It acts as a tumor suppressor gene because MAD2+/-cells enter anaphase early and display chromosome instability, leading to the formation of lung tumors in mice. Complete MAD2 inactivation has not been identified in human tumors, although partial defects are prevalent. By employing RNA interference in human somatic cells, we found that severe reduction of MAD2 protein levels results in mitotic failure and extensive cell death arising from defective spindle formation, incomplete chromosome condensation, and premature mitotic exit leading to multinucleation. Cyclin B is degraded prematurely in the MAD2 short interfering RNA-treated cells but not in MAD2+/-cells, suggesting an explanation for the spindle failure and mitotic catastrophe in the MAD2 knockdown cells. Thus, anaphase-promoting complex substrates exhibit distinct sensitivities in the presence of different MAD2 doses, which in turn determine MAD2's role as either a tumor suppressor or an essential gene.
Keywords: controlled study; human cell; gene deletion; mitosis; cell cycle proteins; cell death; cell cycle; somatic cell; protein degradation; rna interference; transfection; animalia; lung tumor; tumor suppressor gene; base sequence; anaphase; spindle cell; mitosis spindle; microscopy, fluorescence; calcium-binding proteins; cyclin b; chromosomes, human; repressor proteins; genes, tumor suppressor; open reading frames; protein mad2; multinuclear cell; genes, essential; mad2 gene; chromosome condensation; humans; human; priority journal; article
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 101
Issue: 13
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2004-03-30
Start Page: 4459
End Page: 4464
Language: English
DOI: 10.1073/pnas.0306069101
PROVIDER: scopus
PMCID: PMC384769
PUBMED: 15070740
Notes: Proc. Natl. Acad. Sci. U. S. A. -- Cited By (since 1996):118 -- Export Date: 16 June 2014 -- CODEN: PNASA -- Source: Scopus
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MSK Authors
  1. Loren Michel
    15 Michel
  2. Robert Benezra
    134 Benezra