Nutrients and bioenergetics are prerequisites for proliferation and survival of mammalian cells. 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.

译文

营养物质和生物能量学是哺乳动物细胞增殖和存活的先决条件。我们提供的证据表明,细胞周期蛋白依赖性激酶抑制剂p27(Kip1) 在Peutz-Jeghers综合征蛋白AMP激活蛋白激酶 (LKB1-AMPK) 能量感应途径下游的Thr 198被磷酸化,从而提高p27的稳定性,并将营养浓度和生物能学的感知与细胞周期进程直接联系起来。野生型和拟磷Thr的异位表达198于Asp 198 (T198D),但不稳定Thr 198于Ala 198 (p27(T198A)) 足以诱导自噬。在激活LKB1-AMPK途径并随后诱导自噬的应激条件下,p27敲低导致细胞凋亡。因此,在Thr 198处p27的LKB1-AMPK途径依赖性磷酸化稳定p27并允许细胞通过自噬存活生长因子戒断和代谢应激。这可能有助于在生长因子剥夺,营养和能量代谢中断或化疗压力下的肿瘤细胞存活。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录