Apoptotic Cells Activate AMP-activated Protein Kinase (AMPK) and Inhibit Epithelial Cell Growth without Change in Intracellular Energy Stores
Apoptotic Cells Activate AMP-activated Protein Kinase (AMPK) and Inhibit Epithelial Cell Growth without Change in Intracellular Energy Stores
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DOI：
10.1074/jbc.m115.667345
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发表时间：
2015-09-11
影响因子：
4.8
通讯作者：
Levine, Jerrold S.
中科院分区：
文献类型：
--
作者：
Patel, Vimal A.;Massenburg, Donald;Levine, Jerrold S.
细胞凋亡在组织的维持和发育过程中起着不可或缺的作用。我们已经表明，受体介导的识别凋亡的靶细胞由活的肾近端肾小管上皮细胞（PTECs）抑制PTECs的增殖和存活。在这里，我们研究了凋亡靶点对PTEC细胞生长的影响（细胞周期G1期的细胞大小）。使用细胞培养模型，我们表明，凋亡细胞有效地激活AMP激活蛋白激酶（AMPK），细胞内能量储存的高度敏感的传感器。AMPK激活导致其下游靶点核糖体蛋白p70 S6激酶（p70 S6K）活性降低，并伴随细胞生长抑制。重要的是，这些事件发生时细胞内AMP、ADP或ATP水平没有可检测的变化。AMPK的抑制，无论是通过化合物C抑制还是通过shRNA分子抑制，都减少了凋亡靶点的作用，并在很大程度上使p70 S6K活性和细胞大小恢复到正常水平。凋亡靶点还抑制Akt，这是调节细胞生长的第二信号传导途径。组成型活性Akt构建体的表达部分缓解了细胞生长抑制，但不如AMPK的抑制有效。凋亡靶点对细胞生长的抑制依赖于凋亡靶点和PTECs之间的物理相互作用，但不依赖于吞噬作用。我们的结论是受体介导的识别凋亡靶模拟细胞内能量消耗，激活AMPK和抑制细胞生长的影响。通过充当环境变化的哨兵，凋亡性死亡可能使附近的活细胞，特别是非迁移性上皮细胞，能够监测和适应局部压力。
Apoptosis plays an indispensable role in the maintenance and development of tissues. We have shown that receptor-mediated recognition of apoptotic target cells by viable kidney proximal tubular epithelial cells (PTECs) inhibits the proliferation and survival of PTECs. Here, we examined the effect of apoptotic targets on PTEC cell growth (cell size during G1 phase of the cell cycle). Using a cell culture model, we show that apoptotic cells potently activate AMP-activated protein kinase (AMPK), a highly sensitive sensor of intracellular energy stores. AMPK activation leads to decreased activity of its downstream target, ribosomal protein p70 S6 kinase (p70S6K), and concomitant inhibition of cell growth. Importantly, these events occur without detectable change in intracellular levels of AMP, ADP, or ATP. Inhibition of AMPK, either pharmacologically by compound C or molecularly by shRNA, diminishes the effects of apoptotic targets and largely restores p70S6K activity and cell size to normal levels. Apoptotic targets also inhibit Akt, a second signaling pathway regulating cell growth. Expression of a constitutively active Akt construct partially relieved cell growth inhibition but was less effective than inhibition of AMPK. Inhibition of cell growth by apoptotic targets is dependent on physical interaction between apoptotic targets and PTECs but independent of phagocytosis. We conclude that receptor-mediated recognition of apoptotic targets mimics the effects of intracellular energy depletion, activating AMPK and inhibiting cell growth. By acting as sentinels of environmental change, apoptotic death may enable nearby viable cells, especially nonmigratory epithelial cells, to monitor and adapt to local stresses.