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© The Rockefeller University Press, 0021-9525/2003/2/284-a $5.00
The Journal of Cell Biology, Volume 160, Number 3, 284-a-284

A model of missegregation

Cells lacking one copy of Rae1 (bottom) fail to arrest when treated with nocodazole.

Most human tumors have an abnormal number of chromosomes, implying that something has gone wrong with their mitotic checkpoint systems, but the genes encoding checkpoint proteins are rarely mutated in tumor cells. On page 341, Babu et al. provide a possible explanation for this apparent contradiction and describe new mouse models that should be useful in studying cancer progression.The authors disrupted two highly homologous mouse genes, encoding the nuclear transport factor Rae1 and the checkpoint protein Bub3. Homozygous null mutations in either Rae1 or Bub3 are embryonic lethal. Heterozygous mice with only one copy of Rae1 survive, but exhibit mitotic checkpoint defects and chromosome mis-segregation, and are predisposed to carcinogen-induced lung cancer. Heterozygous Bub3 knockout mice have a strikingly similar phenotype. Surprisingly, overexpressing Rae1 in the mice compensates for haploinsufficiency of either Rae1 or Bub3, indicating significant overlap in the two proteins' functions.

The results show that the mammalian mitotic checkpoint system is extremely sensitive to underexpression of its components. Epigenetic effects in tumor cells might start a vicious cycle, in which down-regulation of a checkpoint protein causes chromosome loss, leading to the loss of other checkpoint proteins and further chromosome missegregation. The new strains can now be crossed with existing mouse cancer models to study aneuploidy in tumor pathogenesis.

Alan W. Dove

alanwdove{at}earthlink.net

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Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation

J. Ramesh Babu, Karthik B. Jeganathan, Darren J. Baker, Xiaosheng Wu, Ningling Kang-Decker, and Jan M. van Deursen
J. Cell Biol. 2003 160: 341-353. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF, 1002K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dove, A. W. Search for Related Content PubMed Articles by Dove, A. W. Related Collections Related Article Social Bookmarking                            What's this?