INS and cancer: Consistent with these observations, insulin robustly activates ATF4 in HT22(81) and moderately activates ATF4 in MEFs.(69) Interestingly, mTORC1, another target of Akt, activates ATF4 to subsequently activate purine synthesis in cancer cells.(69) Furthermore, the neuron-specific deletion of TSC2, a negative inhibitor of mTORC1, activates mTORC1 signaling and increases both ATF4 and MTHFD2 gene expression in the brain.(69) The induction of ATF4 by tunicamycin was abolished in Ser51Ala eIF2α mutant knock-in MEFs [eIF2α (A/A) MEFs].