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.
Kalitsis
Paul
P
Chromosome Research Laboratory, Murdoch Childrens Research Institute, Department of Paediatrics, Royal Children's Hospital, Melbourne, Australia.
Fowler
Kerry J
KJ
Griffiths
Belinda
B
Earle
Elizabeth
E
Chow
C W
CW
Jamsen
Kris
K
Choo
K H Andy
KH
D000782:Aneuploidy; D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D043171:Chromosomal Instability / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone; D002874:Chromosome Mapping; D017931:DNA Primers; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000502:physiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D000075223:Poly-ADP-Ribose Binding Proteins
C489445:Bub3 protein, mouse; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D017931:DNA Primers; D000075223:Poly-ADP-Ribose Binding Proteins