Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA.
Neoplasia. 2010 Jan;12(1):61-8. doi: 10.1593/neo.91354.
Hypoxia is a common microenvironment in solid tumors and is correlated with tumor progression by regulating cancer cell survival. Recent studies suggest that activation of double-stranded RNA-dependent protein kinase-like endoplasmic reticulum-related kinase (PERK) and phosphorylation of alpha subunit of eIF2 (eIF2alpha) confer cell adaptation to hypoxic stress. However, eIF2alpha is still phosphorylated at a lowered level in PERK knockout cells under hypoxic conditions. The mechanism for eIF2alpha kinase(s) (eIF2AK)-increased cell survival is not clear. In this report, we provide evidence that another eIF2AK, the amino acid starvation-dependent general control of amino acid biosynthesis kinase (GCN2), is also involved in hypoxia-induced eIF2alpha phosphorylation. We demonstrate that both GCN2 and PERK mediate the cell adaptation to hypoxic stress. High levels of eIF2alpha phosphorylation lead to G(1) arrest and protect cells from hypoxia-induced apoptosis. Reduced phosphorylation of eIF2alpha by knocking out either PERK or GCN2 suppresses hypoxia-induced G(1) arrest and promotes apoptosis in accompany with activation of p53 signal cascade. However, totally abolishing phosphorylation of eIF2alpha inhibits G(1) arrest without promoting apoptosis. On the basis of our results, we propose that the levels of eIF2alpha phosphorylation serve as a "switch" in regulation of G(1) arrest or apoptosis under hypoxic conditions.
缺氧是实体肿瘤中常见的微环境，通过调节癌细胞的存活与肿瘤的进展相关。最近的研究表明，双链 RNA 依赖性蛋白激酶样内质网相关激酶 (PERK) 的激活和真核起始因子 2α(eIF2α) 的磷酸化赋予细胞适应缺氧应激的能力。然而，在缺氧条件下 PERK 敲除细胞中，eIF2α仍处于低水平磷酸化状态。eIF2α 激酶 (eIF2AK) 增加细胞存活的机制尚不清楚。在本报告中，我们提供了证据表明另一种 eIF2AK，即氨基酸饥饿依赖性的氨基酸生物合成普遍调控激酶 (GCN2)，也参与了缺氧诱导的 eIF2α 磷酸化。我们证明 GCN2 和 PERK 均可介导细胞适应缺氧应激。高水平的 eIF2α 磷酸化导致 G1 期阻滞，并保护细胞免受缺氧诱导的凋亡。敲除 PERK 或 GCN2 均可降低 eIF2α 的磷酸化，从而抑制缺氧诱导的 G1 期阻滞并促进凋亡，同时激活 p53 信号级联。然而，完全抑制 eIF2α 的磷酸化会抑制 G1 期阻滞而不促进凋亡。基于我们的结果，我们提出 eIF2α 磷酸化水平在缺氧条件下调节 G1 期阻滞或凋亡中起“开关”作用。
