Mitotic chromosome condensation mediated by the retinoblastoma protein is tumor-suppressive
Mitotic chromosome condensation mediated by the retinoblastoma protein is tumor-suppressive
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DOI：
10.1101/gad.1917610
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发表时间：
2010-07-01
影响因子：
10.5
通讯作者：
Dick, Frederick A.
中科院分区：
文献类型：
--
作者：
Coschi, Courtney H.;Martens, Alison L.;Dick, Frederick A.
有丝分裂染色体的凝聚和分离是细胞繁殖的关键过程，在哺乳动物中，有丝分裂错误可能导致癌症的发生。在这份报告中，我们证明了视网膜母细胞瘤蛋白(PRB)，一个众所周知的通过细胞周期的G1期推进的调节蛋白，在有丝分裂染色体凝聚中发挥着关键作用，而不是依赖于G1到S期的调节。利用基因靶向突变小鼠，我们分离地研究了pRb的这一方面的功能，并证明它是pRb介导的肿瘤抑制的重要组成部分。当pRb浓缩染色体的能力受损时，易患癌症的Trp53(-/-)小鼠会屈服于更具侵袭性的癌症形式。此外，我们证明了由突变的pRb引起的有丝分裂染色体结构缺陷会加速杂合性的丧失，导致Trp53(+/-)小鼠更早的肿瘤形成。这些数据揭示了一种新的抑制肿瘤的机制，即通过有丝分裂染色体的适当凝聚来维持基因组的稳定性。
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.