Crosstalk between the Rb Pathway and AKT Signaling Forms a Quiescence-Senescence Switch
Crosstalk between the Rb Pathway and AKT Signaling Forms a Quiescence-Senescence Switch
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DOI：
10.1016/j.celrep.2014.03.006
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发表时间：
2014-04-01
期刊：
影响因子：
8.8
通讯作者：
Hara, Eiji
中科院分区：
文献类型：
--
作者：
Imai, Yoshinori;Takahashi, Akiko;Hara, Eiji
静止期和衰老期的细胞周期停滞主要是由视网膜母细胞瘤（Rb）肿瘤抑制通路协调的，但静止-衰老转换的潜在机制仍不清楚。在这里，我们表明，Rb-AKT信号通路之间的串扰形成这种开关通过控制FoxO 3a和FoxM 1转录因子在培养的成纤维细胞的重叠功能。在没有促有丝分裂信号的情况下，尽管FoxM 1的表达被Rb通路抑制，但FoxO 3a通过维持SOD 2的表达来防止活性氧（ROS）的产生，从而导致静止。然而，如果Rb通路在促有丝分裂信号的存在下被激活，FoxO 3a也被AKT灭活，从而减少SOD 2表达，从而允许ROS产生。这种情况通过不可修复的DNA损伤加速衰老。我们证明了这一途径在小鼠肝脏中起作用，表明这种机制可能有助于更广泛的体内组织稳态。
Cell-cycle arrest in quiescence and senescence is largely orchestrated by the retinoblastoma (Rb) tumor-suppressor pathway, but the mechanisms underlying the quiescence-senescence switch remain unclear. Here, we show that the crosstalk between the Rb-AKT-signaling pathways forms this switch by controlling the overlapping functions of FoxO3a and FoxM1 transcription factors in cultured fibroblasts. In the absence of mitogenic signals, although FoxM1 expression is repressed by the Rb pathway, FoxO3a prevents reactive oxygen species (ROS) production by maintaining SOD2 expression, leading to quiescence. However, if the Rb pathway is activated in the presence of mitogenic signals, FoxO3a is also inactivated by AKT, thus reducing SOD2 expression and consequently allowing ROS production. This situation elicits senescence through irreparable DNA damage. We demonstrate that this pathway operates in mouse liver, indicating that this machinery may contribute more broadly to tissue homeostasis in vivo.