Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling.

By M. P. DeYoung, P. Horák, Avihu Sofer, D. Sgroi, L. Ellisen. Genes & Development, 2008

755 citations recorded by the source corpus.

Hypoxia induces rapid and dramatic changes in cellular metabolism, in part through inhibition of target of rapamycin (TOR) kinase complex 1 (TORC1) activity. Genetic studies have shown the tuberous sclerosis tumor suppressors TSC1/2 and the REDD1 protein to be essential for hypoxia regulation of TORC1 activity in Drosophila and in mammalian cells. The molecular mechanism and physiologic significance of this effect of hypoxia remain unknown. Here, we demonstrate that hypoxia and REDD1 suppress mammalian TORC1 (mTORC1) activity by releasing TSC2 from its growth factor-induced association with inhibitory 14-3-3 proteins. Endogenous REDD1 is required for both dissociation of endogenous TSC2/14-3-3 and inhibition of mTORC1 in response to hypoxia. REDD1 mutants that fail to bind 14-3-3 are defective in eliciting TSC2/14-3-3 dissociation and mTORC1 inhibition, while TSC2 mutants that do not bind 14-3-3 are inactive in hypoxia signaling to mTORC1. In vitro, loss of REDD1 signaling promotes proliferation and anchorage-independent growth under hypoxia through mTORC1 dysregulation. In vivo, REDD1 loss elicits tumorigenesis in a mouse model, and down-regulation of REDD1 is observed in a subset of human cancers. Together, these findings define a molecular mechanism of signal integration by TSC1/2 that provides insight into the ability of REDD1 to function in a hypoxia-dependent tumor suppressor pathway.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ac8333dfe8ff3c5f315e07beb0c993e8086b876b

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Citations in the corpus

Autophagy as a target for anticancer therapy (2011, background): “Hypoxia can also activate autophagy through HIF1α-independent effects”
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).”
A complex interplay between Akt, TSC2, and the two mTOR complexes (2009, background): “One enticing, but under-studied, mechanism entails 14-3-3-binding to multiple Akt phosphorylation sites on TSC2 [20,21], perhaps leading to changes in its subcellular localization and/or disruption of its association with Rheb.”
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).”
The 14-3-3 proteins: integrators of diverse signaling cues that impact cell fate and cancer development (2008, background): “A report by DeYoung and colleagues describes a mechanism for how expression of REDD1 might modulate TSC2 activity and this mechanism involves 14-3-3 [28].”
mTOR signaling at a glance (2009, background): “REDD1 blocks mTORC1 signaling by releasing TSC2 from its growth-factor-induced association with 14-3-3 proteins (DeYoung et al., 2008).”