Increased chromosome instability but not cancer predisposition in haploinsufficient Bub3 mice

Mitotic spindle checkpoint proteins have been shown to play a crucial role in the accurate segregation of chromosomes during cell division. Bub3 is a member of a group of mitotic checkpoint proteins that are essential for this process. To investigate the role of Bub3 in chromosome segregation and cancer development, we analyzed haploinsufficient cells in mice. Heterozygous Bub3 embryonic fibroblasts displayed increased aneuploidy and premature sister‐chromatid separation. In addition, when challenged with the microtubule disruptor nocodazole, the cells showed a slight increase in chromatid breakage and a decrease in the mitotic index. No substantial differences were observed between wild‐type and Bub3 heterozygous mice in the frequency or the rate at which tumors appeared. Crossing Bub3+/− mice onto a heterozygous tumor‐suppressor background of Trp53 or Rb1 similarly revealed no substantial differences in either the number or the rate at which tumors appeared. These results suggest that haploinsufficiency of Bub3 causes a slight increase in chromosome instability but is not clearly associated with a noticeable rise in the probability of tumor formation in the animal, possibly because of a partially functional mitotic checkpoint, or cells exhibiting chromosome instability could have activated the apoptosis pathway and thus escaped tumor induction and detection. © 2005 Wiley‐Liss, Inc.

[1]  N. Rahman,et al.  Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B , 2004, Nature Genetics.

[2]  Helder Maiato,et al.  Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint. , 2004, Developmental cell.

[3]  R. Kumar,et al.  BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice , 2004, Nature Genetics.

[4]  Viji M. Draviam,et al.  Timing and checkpoints in the regulation of mitotic progression. , 2004, Developmental cell.

[5]  Guido Kroemer,et al.  Cell death by mitotic catastrophe: a molecular definition , 2004, Oncogene.

[6]  Viji M. Draviam,et al.  Chromosome segregation and genomic stability. , 2004, Current opinion in genetics & development.

[7]  E. Dı́az-Rodrı́guez,et al.  Complete loss of the tumor suppressor MAD2 causes premature cyclin B degradation and mitotic failure in human somatic cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Hongtao Yu,et al.  The spindle checkpoint, aneuploidy, and cancer , 2004, Oncogene.

[9]  R. Mahmood,et al.  Slippage of Mitotic Arrest and Enhanced Tumor Development in Mice with BubR1 Haploinsufficiency , 2004, Cancer Research.

[10]  J. Tytell,et al.  Structure, function, and regulation of budding yeast kinetochores. , 2003, Annual review of cell and developmental biology.

[11]  Z. Darżynkiewicz,et al.  BUBR1 deficiency results in abnormal megakaryopoiesis. , 2003, Blood.

[12]  K. Sullivan,et al.  Centromeres and Kinetochores From Epigenetics to Mitotic Checkpoint Signaling , 2003, Cell.

[13]  D. Baker,et al.  Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation , 2003, The Journal of cell biology.

[14]  K. Hardwick,et al.  The awesome power of multiple model systems: interpreting the complex nature of spindle checkpoint signaling. , 2002, Trends in cell biology.

[15]  A. Knudson,et al.  Two genetic hits (more or less) to cancer , 2001, Nature Reviews Cancer.

[16]  W. Gerald,et al.  MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells , 2001, Nature.

[17]  K. Choo,et al.  Bub3 gene disruption in mice reveals essential mitotic spindle checkpoint function during early embryogenesis. , 2000, Genes & development.

[18]  P. Sorger,et al.  Chromosome Missegregation and Apoptosis in Mice Lacking the Mitotic Checkpoint Protein Mad2 , 2000, Cell.

[19]  S. Sen,et al.  Aneuploidy and cancer , 2000, Current opinion in oncology.

[20]  Bert Vogelstein,et al.  Mutations of mitotic checkpoint genes in human cancers , 1998, Nature.

[21]  R. Weinberg,et al.  Tumor spectrum analysis in p53-mutant mice , 1994, Current Biology.

[22]  A. Berns,et al.  Requirement for a functional Rb-1 gene in murine development , 1992, Nature.

[23]  R. Weinberg,et al.  Effects of an Rb mutation in the mouse , 1992, Nature.

[24]  A. Bradley,et al.  Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis , 1992, Nature.

[25]  P. Stukenberg,et al.  Analyzing the spindle checkpoint in yeast and frogs. , 2004, Methods in molecular biology.