Work from Ozcan et al. weaves the unfolded protein response (UPR) [which is initiated in the endoplasmic reticulum (ER) when the capacity of the ER to produce properly folded proteins is exceeded] into a regulatory network regulating insulin signaling and apoptosis. The paper focuses on signaling through the mTORC1 complex, which regulates protein synthesis by controlling the activity of ribosomal protein S6 kinases and eukaryotic initiation factor 4E. Deletion or loss of function of the tuberous sclerosis complex genes (TSC1 and TSC2) leads to sustained activation of mTORC1. In mouse embryo fibroblasts lacking TSC1 and TSC2 or in tumor cells from Tsc2+/– mice, the UPR response was activated. This UPR-dependent activation of the mitogen-activated protein kinase JNK and serine/threonine phosphorylation of insulin receptor substrate 1 provided a mechanism by which insulin receptor signaling was inhibited. Treatments that alleviated ER stress (such as the addition of a chemical chaperone that promoted proper protein folding) alleviated the defects in insulin signaling in Tsc1–/– or Tsc2–/– cells. When ER stress gets really out of hand, cells undergo apoptosis, and the authors showed that TSC-deficient cells had increased vulnerability to apoptosis when treated with chemical agents that enhance ER stress. The authors and Reiling and Sabatini in associated commentary discuss the appealing logic of having the UPR feed back onto the mTORC1 pathway, which responds to nutrients and regulates growth and proliferation, thus coordinating pathways regulating metabolism and survival. They further point out the possibility that the UPR may provide a target to promote elimination of tumor cells, specifically those cells lacking TSC proteins, or more generally in tumor cells whose rapid growth and high rates of protein synthesis might make them more vulnerable than normal cells.
U. Ozcan, L. Ozcan, E. Yilmaz, K. Düvel, M. Sahin, B. D. Manning, G. S. Hotamisligil, Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol. Cell 29, 541-551 (2008). [PubMed]
J. H. Reiling, D. M. Sabatini, Increased mTORC1 signaling UPRegulates stress. Mol. Cell 29, 533-535 (2008). [PubMed]