Hyper-mitogenic drive coexists with mitotic incompetence in senescent cells.
Hyper-mitogenic drive coexists with mitotic incompetence in senescent cells.
复制标题
DOI：
10.4161/cc.22937
复制
发表时间：
2012-12-15
期刊：
影响因子：
--
通讯作者：
Blagosklonny MV
中科院分区：
文献类型：
--
作者：
Leontieva OV;Lenzo F;Demidenko ZN;Blagosklonny MV
当细胞周期被阻止时，即使促进生长的途径如mTOR仍然活跃，细胞也会衰老。例如，p21或p16的诱导使细胞周期停滞而不抑制mTOR，这反过来将p21/p16诱导的停滞转化为衰老（衰老转化）。在这里，我们表明，老年转换是伴随着细胞周期蛋白D1的急剧积累，其次是细胞周期蛋白E和复制应激。当p21被关闭时，衰老细胞（尽管它们丧失了增殖潜力）通过S期进展，并且细胞周期蛋白D1和E的水平下降。大多数细胞进入有丝分裂，然后死亡，要么在有丝分裂停滞期间，要么在有丝分裂滑动后，要么经历核内复制。接下来，我们研究了mTOR的抑制是否会阻止p21阻滞细胞中细胞周期蛋白的积累和有丝分裂能力的丧失。nutlin-3抑制这些细胞中的mTOR，雷帕霉素在p21诱导的停滞期间抑制衰老转化，减缓细胞周期蛋白D1和E的积累，并降低复制应激。当p21被关闭时，细胞成功地通过S期和有丝分裂。此外，衰老的小鼠胚胎成纤维细胞（MEFs）过表达细胞周期蛋白D1。从细胞周期停滞释放后，衰老的MEFs进入S期，但不能进行有丝分裂，不增殖。我们的结论是，细胞衰老的特点是徒劳的超有丝分裂驱动与mTOR依赖的有丝分裂不全。
When the cell cycle is arrested, even though growth-promoting pathways such as mTOR are still active, then cells senesce. For example, induction of either p21 or p16 arrests the cell cycle without inhibiting mTOR, which, in turn, converts p21/p16-induced arrest into senescence (geroconversion). Here we show that geroconversion is accompanied by dramatic accumulation of cyclin D1 followed by cyclin E and replicative stress. When p21 was switched off, senescent cells (despite their loss of proliferative potential) progressed through S phase, and levels of cyclins D1 and E dropped. Most cells entered mitosis and then died, either during mitotic arrest or after mitotic slippage, or underwent endoreduplication. Next, we investigated whether inhibition of mTOR would prevent accumulation of cyclins and loss of mitotic competence in p21-arrested cells. Both nutlin-3, which inhibits mTOR in these cells, and rapamycin suppressed geroconversion during p21-induced arrest, decelerated accumulation of cyclins D1 and E and decreased replicative stress. When p21 was switched off, cells successfully progressed through both S phase and mitosis. Also, senescent mouse embryonic fibroblasts (MEFs) overexpressed cyclin D1. After release from cell cycle arrest, senescent MEFs entered S phase but could not undergo mitosis and did not proliferate. We conclude that cellular senescence is characterized by futile hyper-mitogenic drive associated with mTOR-dependent mitotic incompetence.
登录
查看更多内容
DOI：
10.18632/aging.100443
发表时间：
2012-03
期刊：
Aging
影响因子：
--
作者：
Blagosklonny MV
通讯作者：
Blagosklonny MV
影响因子：
4.3
作者：
Demidenko, Zoya N.;Shtutman, Michael;Blagosklonny, Mikhail V.
通讯作者：
Blagosklonny, Mikhail V.
影响因子：
11.2
作者：
Bagheri-Yarmand, Rozita;Biernacka, Anna;Keyomarsi, Khandan
通讯作者：
Keyomarsi, Khandan
DOI：
10.18632/aging.100165
发表时间：
2010-06
期刊：
Aging
影响因子：
--
作者：
Darzynkiewicz Z
通讯作者：
Darzynkiewicz Z
影响因子：
7.5
作者：
Dazert, Eva;Hall, Michael N.
通讯作者：
Hall, Michael N.