Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex.

By J. Brugarolas, Kui Lei, Rebecca L. Hurley, B. Manning, J. Reiling, E. Hafen, L. Witters, L. Ellisen, W. Kaelin. Genes & Development, 2004

1,421 citations recorded by the source corpus.

Mammalian target of rapamycin (mTOR) is a central regulator of protein synthesis whose activity is modulated by a variety of signals. Energy depletion and hypoxia result in mTOR inhibition. While energy depletion inhibits mTOR through a process involving the activation of AMP-activated protein kinase (AMPK) by LKB1 and subsequent phosphorylation of TSC2, the mechanism of mTOR inhibition by hypoxia is not known. Here we show that mTOR inhibition by hypoxia requires the TSC1/TSC2 tumor suppressor complex and the hypoxia-inducible gene REDD1/RTP801. Disruption of the TSC1/TSC2 complex through loss of TSC1 or TSC2 blocks the effects of hypoxia on mTOR, as measured by changes in the mTOR targets S6K and 4E-BP1, and results in abnormal accumulation of Hypoxia-inducible factor (HIF). In contrast to energy depletion, mTOR inhibition by hypoxia does not require AMPK or LKB1. Down-regulation of mTOR activity by hypoxia requires de novo mRNA synthesis and correlates with increased expression of the hypoxia-inducible REDD1 gene. Disruption of REDD1 abrogates the hypoxia-induced inhibition of mTOR, and REDD1 overexpression is sufficient to down-regulate S6K phosphorylation in a TSC1/TSC2-dependent manner. Inhibition of mTOR function by hypoxia is likely to be important for tumor suppression as TSC2-deficient cells maintain abnormally high levels of cell proliferation under hypoxia.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1ee17150c59567129f1d4a88b259f8b578269936

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Citations in the corpus

Hypoxia-Induced Autophagy Is Mediated through Hypoxia-Inducible Factor Induction of BNIP3 and BNIP3L via Their BH3 Domains (2009, background): “Although hypoxia reduces the activity of mTOR via the induction of Redd1 (5) and also via a direct link between BNIP3 and Rheb (16), this action could contribute to weakening the Bcl-2–Beclin1 complex but cannot account for the pronounced autophagy observed under hypoxic conditions.”
mTOR signaling in growth control and disease (2012, positive): “Hypoxia also induces the expression of transcriptional regulation of DNA damage response 1 (REDD1), which activates TSC2 function in a still poorly understood manner (Brugarolas et al., 2004; DeYoung et al., 2008; Reiling and Hafen, 2004).”
The LKB1-AMPK pathway: metabolism and growth control in tumor suppression (2009, neutral): “Consistent with earlier studies in TSC-deficient fibroblast”
Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. (2008, background): “We showed previously that TSC2 cells demonstrated a proliferation advantage specifically under hypoxic conditions compared with wild-type cells, and that this advantage was attributable to elevated mTORC1 activity (Brugarolas et al. 2004).”
Hypoxia signalling in cancer and approaches to enforce tumour regression (2006, background): “; and second, a more direct link between HIF and mTOR was established in Drosophila , in which the HIF-induced paralogue gene products, Scylla and Charybdis (REDD1/RTP801 in mammals), activate the TSC complex resulting in mTOR inhibitio”
PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. (2007, background): “, 2003a), and hypoxia and stress sensing (Brugarolas et al., 2004; Corradetti et al., 2005; Reiling and Hafen, 2004) all regulate TSC1-TSC2 activity and the GTP loading of rheb.”
Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. (2011, background): “Our observations demonstrate that REDD1, is a mediator of metformininduced cell cycle arrest in prostate cancer cells and is one of the component of a critical pathway for human tumor suppression (12, 13).”
Regulation Mechanisms and Signaling Pathways of Autophagy (2009, background): “In addition, hypoxia inhibits TOR and blocks eIF4F (eukaryotic initiation factor 4F) complex formation and mRNA translation (7,123).”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “Similarly, hypoxia inhibits mTORC1 in part through AMPK activation, but also through the induction of REDD1 (Regulated in DNA damage and development 1), which activates TSC (Brugarolas et al., 2004).”
NORMALIZATION OF THE VASCULATURE FOR TREATMENT OF CANCER AND OTHER DISEASES (2011, neutral): “In addition, mTOR signaling plays a role in VEGF synthesis, through both regulation of HIF-1 (134) and due to its own regulation by the tuberous sclerosis complex TSC1/2 (41, 42).”
mTOR: a pharmacologic target for autophagy regulation. (2015, positive): “Low cellular oxygen levels also inhibit mTORC1 by upregulating DNA damage response 1 (REDD1), which may modulate TSC2 activity to inhibit mTORC1 (31, 32).”
Regulation of Immune Responses by mTOR (2011, background): “Finally, the hypoxia-induced factor protein regulated in the development of DNA damage response 1 (REDD1) can inhibit mTOR by promoting the assembly and activation of TSC in the setting of low oxygen (32).”