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Published 22 December 2003. doi:10.1083/jcb.200306153
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© The Rockefeller University Press, 0021-9525/2003/12/1231 $8.00
The Journal of Cell Biology, Volume 163, Number 6, 1231-1242

Article

Spindle checkpoint proteins Mad1 and Mad2 are required for cytostatic factor–mediated metaphase arrest



Brian J. Tunquist, Patrick A. Eyers, Lin G. Chen, Andrea L. Lewellyn and James L. Maller

Howard Hughes Medical Institute and Department of Pharmacology, University of Colorado School of Medicine, Denver, CO 80262

Address correspondence to James L. Maller, HHMI and Department of Pharmacology, University of Colorado School of Medicine, 4200 E. 9th Avenue, Campus Box C236, Denver, CO 80262. Tel.: (303) 315-7075. Fax: (303) 315-7160. email: Jim.Maller{at}UCHSC.edu

In cells containing disrupted spindles, the spindle assembly checkpoint arrests the cell cycle in metaphase. The budding uninhibited by benzimidazole (Bub) 1, mitotic arrest-deficient (Mad) 1, and Mad2 proteins promote this checkpoint through sustained inhibition of the anaphase-promoting complex/cyclosome. Vertebrate oocytes undergoing meiotic maturation arrest in metaphase of meiosis II due to a cytoplasmic activity termed cytostatic factor (CSF), which appears not to be regulated by spindle dynamics. Here, we show that microinjection of Mad1 or Mad2 protein into early Xenopus laevis embryos causes metaphase arrest like that caused by Mos. Microinjection of antibodies to either Mad1 or Mad2 into maturing oocytes blocks the establishment of CSF arrest in meiosis II, and immunodepletion of either protein blocked the establishment of CSF arrest by Mos in egg extracts. A Mad2 mutant unable to oligomerize (Mad2 R133A) did not cause cell cycle arrest in blastomeres or in egg extracts. Once CSF arrest has been established, maintenance of metaphase arrest requires Mad1, but not Mad2 or Bub1. These results suggest a model in which CSF arrest by Mos is mediated by the Mad1 and Mad2 proteins in a manner distinct from the spindle checkpoint.

Key Words: MAPK; Mad; spindle assembly checkpoint; mitosis; Bub1

Abbreviations used in this paper: APC/C, anaphase-promoting complex/cyclosome; Bub, budding uninhibited by benzimidazole; CSF, cytostatic factor; Emi1, early mitotic inhibitor 1; Mad, mitotic arrest deficient; MEK1, MAPK/Erk kinase 1; p90Rsk, 90-kD ribosomal protein S6 kinase.


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