The energy sensing LKB1-AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis
The energy sensing LKB1-AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis
复制标题
DOI：
10.1038/ncb1537
复制
发表时间：
2007-02-01
影响因子：
21.3
通讯作者：
Mills, Gordon B.
中科院分区：
文献类型：
--
作者：
Liang, Jiyong;Shao, Shan H.;Mills, Gordon B.
营养素和生物能量学是哺乳动物细胞增殖和存活的先决条件(1，2)。我们提出的证据表明，细胞周期蛋白依赖的激酶抑制物p27(Kip1)在Peutz-Jeghers综合征蛋白-AMPK(LKB1-AMPK)能量敏感通路下游的Thr198处被磷酸化，从而增加了p27的稳定性，并将营养浓度和生物能量学的感知与细胞周期进展直接联系起来。野生型和拟磷化型苏氨酸198到天冬氨酸198(T198D)的异位表达，但不稳定的苏氨酸198到丙氨酸198(p27(T198A))的异位表达足以诱导自噬。在激活LKB1-AMPK通路并随后诱导自噬的应激条件下，p27基因敲除会导致细胞凋亡。因此，依赖于LKB1-AMPK通路的p27在Thr198处的磷酸化稳定了p27，并允许细胞通过自噬在生长因子停用和代谢应激中存活下来。这可能有助于肿瘤细胞在生长因子被剥夺、营养和能量代谢中断的情况下存活，或者在化疗压力下存活。
Nutrients and bioenergetics are prerequisites for proliferation and survival of mammalian cells(1,2). We present evidence that the cyclin-dependent kinase inhibitor p27(Kip1), is phosphorylated at Thr 198 downstream of the Peutz-Jeghers syndrome protein-AMP-activated protein kinase (LKB1-AMPK) energy-sensing pathway, thereby increasing p27 stability and directly linking sensing of nutrient concentration and bioenergetics to cell-cycle progression. Ectopic expression of wild-type and phosphomimetic Thr 198 to Asp 198 (T198D), but not unstable Thr 198 to Ala 198 (p27(T198A)) is sufficient to induce autophagy. Under stress conditions that activate the LKB1-AMPK pathway with subsequent induction of autophagy, p27 knockdown results in apoptosis. Thus LKB1-AMPK pathway-dependent phosphorylation of p27 at Thr 198 stabilizes p27 and permits cells to survive growth factor withdrawal and metabolic stress through autophagy. This may contribute to tumour-cell survival under conditions of growth factor deprivation, disrupted nutrient and energy metabolism, or during stress of chemotherapy.