Mitotic chromosome condensation mediated by the retinoblastoma protein is tumor-suppressive

被引:93
作者
Coschi, Courtney H. [1 ,2 ]
Martens, Alison L. [1 ,2 ]
Ritchie, Kieran [2 ,3 ]
Francis, Sarah M. [1 ,2 ]
Chakrabarti, Subrata [4 ]
Berube, Nathalie G. [3 ,4 ,5 ]
Dick, Frederick A. [1 ,3 ,4 ,5 ]
机构
[1] Univ Western Ontario, London Reg Canc Program, London, ON N6A 4L6, Canada
[2] Univ Western Ontario, Dept Biochem, London, ON N6A 4L6, Canada
[3] Univ Western Ontario, Childrens Hlth Res Inst, London, ON N6A 4L6, Canada
[4] Univ Western Ontario, Dept Pathol, London, ON N6A 4L6, Canada
[5] Univ Western Ontario, Dept Pediat, London, ON N6A 4L6, Canada
基金
加拿大自然科学与工程研究理事会;
关键词
Cohesion; condensation; chromosome instability; cell cycle; chromatin; GROWTH-FACTOR-BETA; POLYMERASE-I TRANSCRIPTION; CELL-CYCLE PROGRESSION; MAMMARY-GLAND; DNA-DAMAGE; GENE; MICE; PRB; MOUSE; P53;
D O I
10.1101/gad.1917610
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:1351 / 1363
页数:13
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