Induction of the C/EBP homologous protein (CHOP) by amino acid deprivationrequires insulin-like growth factor I, phosphatidylinositol 3-kinase, and mammalian target of rapamycin signaling

In mammalian cells, gene regulation by amino acid deprivation is poorly und erstood. Here, we examined the signaling pathways involved in the induction of the C/EBP homologous protein (CHOP) by amino acid starvation. CHOP is a transcription factor that heterodimerizes with other C/EBP family members and may inhibit or activate the transcription of target genes depending on their sequence-specific elements. Amino acid deficiency, when accompanied b y insulin-like growth factor I signaling, results in the accumulation of CH OP messenger RNA and protein in AKR-2B and NIH-3T3 cells. The phosphatidyli nositol 3-kinase inhibitors wortmannin and LY294002 are able to block CHOP induction in response to amino acid deprivation. Rapamycin is also able to abrogate CHOP expression, suggesting that the mammalian target of rapamycin is involved in CHOP induction by amino acid deficiency. LY294002 and rapam ycin are also able to block CHOP induction by hydrogen peroxide, but do not affect expression induced by sodium arsenite or A23187. This is the first evidence that the insulin-like growth factor I/phosphatidylinositol 3-kinas e/mammalian target of rapamycin pathway is required for gene regulation by amino acid deprivation and that this pathway is involved in the induction o f CHOP by both amino acid deficiency and oxidative stress by hydrogen perox ide.