MEK drives cyclin D1 hyperelevation during geroconversion
MEK drives cyclin D1 hyperelevation during geroconversion
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DOI：
10.1038/cdd.2013.86
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发表时间：
2013-09-01
影响因子：
12.4
通讯作者：
Blagosklonny, M. V.
中科院分区：
文献类型：
--
作者：
Leontieva, O. V.;Demidenko, Z. N.;Blagosklonny, M. V.
当细胞周期停滞时，MTOR（雷帕霉素的机械靶标）将可逆停滞转化为衰老（衰老转化）。细胞周期蛋白D1的过表达是衰老的通用标志物，沿着肥大、β-Gal染色和复制/再生潜能（RP）的丧失，即当细胞周期被释放时重新开始增殖的能力。抑制MTOR可减慢衰老转换，尽管仅部分降低细胞周期蛋白D1。在这里，我们表明，在p21和p16诱导的衰老，丝裂原活化/细胞外信号调节激酶（MEK）的抑制剂（U 0126，PD 184352和siRNA）完全阻止细胞周期蛋白D1的积累，使其无法检测。我们还使用了其中MEK抑制剂不抑制MTOR的MEL 10细胞。在这些细胞中，U 0126本身诱导衰老，这是显着的细胞周期蛋白D1阴性。相反，PD 0332991对细胞周期蛋白依赖性激酶（CDK）4/6的抑制导致MEL 10细胞中细胞周期蛋白D1阳性衰老。这两种类型的衰老都被雷帕霉素抑制，将其转化为可逆的停滞。我们证实，CDK 4/6的抑制剂引起细胞周期蛋白D1的阳性衰老在正常的RPE细胞，而U 0126阻止细胞周期蛋白D1的表达。通过siRNA消除细胞周期蛋白D1并不能阻止与其对MTOR缺乏作用相一致的其他衰老标志物。我们的数据证实，仅仅抑制细胞周期就足以引起衰老，只要MTOR是活性的，并且抑制MEK以细胞类型依赖性方式部分抑制MTOR。第二，衰老的标志可能是分离的，和hyperelevated细胞周期蛋白D1，衰老细胞过度活化的标志，并不一定决定其他衰老的标志。第三，无论MTOR如何，MEK的抑制足以消除细胞周期蛋白D1。
When the cell cycle becomes arrested, MTOR (mechanistic Target of Rapamycin) converts reversible arrest into senescence (geroconversion). Hyperexpression of cyclin D1 is a universal marker of senescence along with hypertrophy, beta-Gal staining and loss of replicative/regenerative potential (RP), namely, the ability to restart proliferation when the cell cycle is released. Inhibition of MTOR decelerates geroconversion, although only partially decreases cyclin D1. Here we show that in p21- and p16-induced senescence, inhibitors of mitogen-activated/extracellular signal-regulated kinase (MEK) (U0126, PD184352 and siRNA) completely prevented cyclin D1 accumulation, making it undetectable. We also used MEL10 cells in which MEK inhibitors do not inhibit MTOR. In such cells, U0126 by itself induced senescence that was remarkably cyclin D1 negative. In contrast, inhibition of cyclin-dependent kinase (CDK) 4/6 by PD0332991 caused cyclin D1-positive senescence in MEL10 cells. Both types of senescence were suppressed by rapamycin, converting it into reversible arrest. We confirmed that the inhibitor of CDK4/6 caused cyclin D1 positive senescence in normal RPE cells, whereas U0126 prevented cyclin D1 expression. Elimination of cyclin D1 by siRNA did not prevent other markers of senescence that are consistent with the lack of its effect on MTOR. Our data confirmed that a mere inhibition of the cell cycle was sufficient to cause senescence, providing MTOR was active, and inhibition of MEK partially inhibited MTOR in a cell-type-dependent manner. Second, hallmarks of senescence may be dissociated, and hyperelevated cyclin D1, a marker of hyperactivation of senescent cells, did not necessarily determine other markers of senescence. Third, inhibition of MEK was sufficient to eliminate cyclin D1, regardless of MTOR.