Regulation of G₁ arrest and apoptosis in hypoxia by PERK and GCN2-mediated eIF2α phosphorylation

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 α subunit of eIF2 (eIF2α) confer cell adaptation to hypoxic stress. However, eIF2α is still phosphorylated at a lowered level in PERK knockout cells under hypoxic conditions. The mechanism for eIF2α 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 eIF2α phosphorylation. We demonstrate that both GCN2 and PERK mediate the cell adaptation to hypoxic stress. High levels of eIF2α phosphorylation lead to G₁ arrest and protect cells from hypoxia-induced apoptosis. Reduced phosphorylation of eIF2α by knocking out either PERK or GCN2 suppresses hypoxia-induced G₁ arrest and promotes apoptosis in accompany with activation of p53 signal cascade. However, totally abolishing phosphorylation of eIF2α inhibits G₁ arrest without promoting apoptosis. On the basis of our results, we propose that the levels of eIF2α phosphorylation serve as a "switch" in regulation of G₁ arrest or apoptosis under hypoxic conditions.