ATF4 and neoplasm: The functional importance of PERK as a cytoprotective mediator against hypoxia-induced cell death has been supported by previous studies showing that abrogation of PERK-eIF2α-ATF4 signaling in tumor cells (e.g., PERK−/− mice cells expressing dominant-negative PERK allele or inactive eIF2α mutant) results in a decrease in cell viability and clonogenic capability under hypoxia [198–200].