title: Cellular adaptation to nutrient deprivation: crosstalk between the mTORC1 and eIF2α signaling pathways and implications for autophagy.
abstract: The hostile tumor microenvironment results in the generation of intracellular stresses including hypoxia and nutrient deprivation. In order to adapt to such conditions, the cell utilizes several stress-response mechanisms, including the attenuation of protein synthesis, the inhibition of cellular proliferation, and induction of autophagy. Autophagy leads to the degradation of cellular contents, including damaged organelles and mutant proteins, which the cell can then use as an alternate energy source. Two integral changes to the signaling milieu to promote such a response include inhibition of the mammalian target of rapamycin complex 1 (mTORC1) and phosphorylation of eIF2α. This review will describe how conditions found in the tumor microenvironment regulate mTORC1 as well as eIF2α, the downstream impact of these modifications, and the implications in tumorigenesis. We will then discuss the remarkable similarities and overlapping function of these 2 signaling pathways, focusing on the response to amino acid deprivation, and present a new model involving crosstalk between them based on our recent work.
authors.affiliation: a Department of Biochemistry and Molecular Pharmacology ; New York University School of Medicine , New York , NY USA.
authors.forename: Jordan C
authors.initials: JC
authors.lastname: Wengrod
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Gardner
mesh_terms: D000222:Adaptation, Physiological; D001343:Autophagy; D015852:Eukaryotic Initiation Factor-2 / Q000502:physiology*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D015852:Eukaryotic Initiation Factor-2; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: PP6C; autophagy; eIF2α; integrated stress response; mTORC1; unfolded protein response