Mitotic chromosome condensation mediated by the retinoblastoma protein is tumor-suppressive.
Condensation and segregation of mitotic chromosomes is a critical process for cellular propagation, and, in mammals, mitotic errors can contribute to the pathogenesis of cancer. In this report, we demonstrate that the retinoblastoma protein (pRB), a well-known regulator of progression through the G1 phase of the cell cycle, plays a critical role in mitotic chromosome condensation that is independent of G1-to-S-phase regulation. Using gene targeted mutant mice, we studied this aspect of pRB function in isolation, and demonstrate that it is an essential part of pRB-mediated tumor suppression. Cancer-prone Trp53(-/-) mice succumb to more aggressive forms of cancer when pRB's ability to condense chromosomes is compromised. Furthermore, we demonstrate that defective mitotic chromosome structure caused by mutant pRB accelerates loss of heterozygosity, leading to earlier tumor formation in Trp53(+/-) mice. These data reveal a new mechanism of tumor suppression, facilitated by pRB, in which genome stability is maintained by proper condensation of mitotic chromosomes.
Coschi
Courtney H
CH
London Regional Cancer Program, University of Western Ontario, London, Ontario, Canada.
Martens
Alison L
AL
Ritchie
Kieran
K
Francis
Sarah M
SM
Chakrabarti
Subrata
S
Berube
Nathalie G
NG
Dick
Frederick A
FA
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D043171:Chromosomal Instability / Q000235:genetics; D020090:Chromosome Segregation; D003469:Culture; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D051379:Mice; D008938:Mitosis / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000378:metabolism*; D010641:Phenotype; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D002843:Chromatin; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins