Regulation of G(1) Arrest and Apoptosis in Hypoxia by PERK and GCN2-Mediated eIF2 alpha 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 a subunit of eIF2 (eIF2 alpha) confer cell adaptation to hypoxic stress. However, eIF2 alpha is still phosphorylated at a lowered level in PERK knockout cells under hypoxic conditions. The mechanism for eIF2 alpha 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 eIF2 alpha phosphorylation. We demonstrate that both GCN2 and PERK mediate the cell adaptation to hypoxic stress. High levels of eIF2 alpha phosphorylation lead to G(1) arrest and protect cells from hypoxia-induced apoptosis. Reduced phosphorylation of eIF2 alpha 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 eIF2 alpha inhibits G(1) arrest without promoting apoptosis. On the basis of our results, we propose that the levels of eIF2 alpha phosphorylation serve as a switch in regulation of G(1) arrest or apoptosis under hypoxic conditions.