Baker Darren J, Jeganathan Karthik B, Malureanu Liviu, Perez-Terzic Carmen, Terzic Andre, van Deursen Jan M A
Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA.
J Cell Biol. 2006 Feb 13;172(4):529-40. doi: 10.1083/jcb.200507081.
Aging is a highly complex biological process that is believed to involve multiple mechanisms. Mice that have small amounts of the mitotic checkpoint protein BubR1 age much faster than normal mice, but whether other mitotic checkpoint genes function to prevent the early onset of aging is unknown. In this study, we show that several aging-associated phenotypes appear early in mice that are double haploinsufficient for the mitotic checkpoint genes Bub3 and Rae1 but not in mice that are single haploinsufficient for these genes. Mouse embryonic fibroblasts (MEFs) from Bub3/Rae1 haploinsufficient mice undergo premature senescence and accumulate high levels of p19, p53, p21, and p16, whereas MEFs from single haploinsufficient mice do not. Furthermore, although BubR1 hypomorphic mice have less aneuploidy than Bub3/Rae1 haploinsufficient mice, they age much faster. Our findings suggest that early onset of aging-associated phenotypes in mice with mitotic checkpoint gene defects is linked to cellular senescence and activation of the p53 and p16 pathways rather than to aneuploidy.
衰老 是 一个 高度 复杂 的 生物学 过程，据信 涉及 多种 机制。携带少量有丝分裂检查点蛋白BubR1的小鼠比正常小鼠衰老得快得多，但其他有丝分裂检查点基因是否具有预防衰老早期发生的功能尚不清楚。在本研究中，我们发现，对于有丝分裂检查点基因Bub3和Rae1双单倍剂量不足的小鼠，几种与衰老相关的表型出现得较早，但对于这些基因单倍剂量不足的小鼠则不然。来自Bub3/Rae1单倍剂量不足小鼠的小鼠胚胎成纤维细胞（MEF）会过早衰老，并积累高水平的p19、p53、p21和p16，而来自单倍剂量不足小鼠的MEF则不会。此外，尽管BubR1亚效等位基因小鼠的非整倍体比Bub3/Rae1单倍剂量不足小鼠少，但它们衰老得更快。我们的研究结果表明，有丝分裂检查点基因缺陷小鼠中衰老相关表型的早期出现与细胞衰老以及p53和p16通路的激活有关，而不是与非整倍体有关。
