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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.

SUBMITTER: Michel L 

PROVIDER: S-EPMC384769 | biostudies-literature | 2004 Mar

REPOSITORIES: biostudies-literature

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

Michel Loren L   Diaz-Rodriguez Elena E   Narayan Gopeshwar G   Hernando Eva E   Murty Vundavalli V V S VV   Benezra Robert R  

Proceedings of the National Academy of Sciences of the United States of America 20040315 13


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 fa  ...[more]

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