Enhanced genomic instabilities caused by deregulated microtubule dynamics and chromosome segregation: a perspective from genetic studies in mice.
Aneuploidy is defined as numerical abnormalities of chromosomes and is frequently (>90%) present in solid tumors. In general, tumor cells become increasingly aneuploid with tumor progression. It has been proposed that enhanced genomic instability at least contributes significantly to, if not requires, tumor progression. Two major modes for genomic instability are microsatellite instability (MIN) and chromosome instability (CIN). MIN is associated with DNA-level defects (e.g. mismatch repair defects), and CIN is associated with mitotic errors such as chromosome mis-segregation. The mitotic spindle assembly checkpoint (SAC) ensures that cells with defective mitotic spindles or defective interaction between the spindles and kinetochores do not initiate chromosomal segregation during mitosis. Thus, the SAC functions to protect the cell from chromosome mis-segregation and anueploidy during cell division. A loss of the SAC function results in gross aneuploidy, a condition from which cells with an advantage for proliferation will be selected. During the past several years, a flurry of genetic studies in mice and humans strongly support the notion that an impaired SAC causes enhanced genomic instabilities and tumor development. This review article summarizes the roles of key spindle checkpoint proteins {i.e. Mad1/Mad1L1, Mad2/Mad2L1, BubR1/Bub1B, Bub3/Bub3 [conventional protein name (yeast or human)/mouse protein name]} and the modulators (i.e. Chfr/Chfr, Rae1/Rae1, Nup98/Nup98, Cenp-E/CenpE, Apc/Apc) in genomic stability and suppression of tumor development, with a focus on information from genetically engineered mouse model systems. Further elucidation of molecular mechanisms of the SAC signaling has the potential for identifying new targets for rational anticancer drug design.
Rao
Chinthalapally V
CV
Department of Medicine, Hematology/Oncology Section, University of Oklahoma Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. cv-rao@ouhsc.edu
Yamada
Hiroshi Y
HY
Yao
Yixin
Y
Dai
Wei
W
D011125:Adenomatous Polyposis Coli / Q000235:genetics; D000818:Animals; D002135:Calcium-Binding Proteins / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology; D043171:Chromosomal Instability; D020090:Chromosome Segregation; D004195:Disease Models, Animal; D042822:Genomic Instability; D006801:Humans; D064246:Mad2 Proteins; D051379:Mice; D008870:Microtubules / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology; D009369:Neoplasms / Q000235:genetics*; D028861:Nuclear Pore Complex Proteins / Q000502:physiology; D009687:Nuclear Proteins / Q000502:physiology; D000075223:Poly-ADP-Ribose Binding Proteins; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology; D008941:Spindle Apparatus / Q000502:physiology; D044767:Ubiquitin-Protein Ligases
C489444:BUB3 protein, human; C584278:Bub1b protein, mouse; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; C501384:MAD1L1 protein, human; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D009363:Neoplasm Proteins; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; C465451:Nup98 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D012097:Repressor Proteins; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases