Journal article
Cell-type-dependent regulation of mTORC1 by REDD1 and the tumor suppressors TSC1/TSC2 and LKB1 in response to hypoxia
Molecular and cellular biology, Vol.31(9), pp.1870-1884
05/2011
DOI: 10.1128/MCB.01393-10
PMCID: PMC3133225
PMID: 21383064
Abstract
mTORC1 is a critical regulator of cell growth that integrates multiple signals and is deregulated in cancer. We previously reported that mTORC1 regulation by hypoxia involves Redd1 and the Tsc1/Tsc2 complex. Here we show that Redd1 induction by hypoxia is tissue dependent and that hypoxia signals are relayed to mTORC1 through different pathways in a tissue-specific manner. In the liver, Redd1 induction is restricted to the centrilobular area, and in primary hepatocytes, mTORC1 inhibition by hypoxia is independent of Redd1. Furthermore, Tsc1/Tsc2 and Arnt (Hif-1β) are similarly dispensable. Hypoxia signaling in hepatocytes involves Lkb1, AMP-activated protein kinase (AMPK), and raptor. Differences in signal relay extend beyond hypoxia and involve AMPK signaling. AMPK activation (using 5-aminoimidazole-4-carboxamide riboside [AICAR]) induces raptor phosphorylation and inhibits mTORC1 in both mouse embryo fibroblasts (MEFs) and hepatocytes, but whereas mTORC1 inhibition is Tsc1/Tsc2 dependent in MEFs, it is independent in hepatocytes. In liver cells, raptor phosphorylation is essential for both AMPK and hypoxia signaling. Thus, context-specific signals are required for raptor phosphorylation-induced mTORC1 inhibition. Our data illustrate a heretofore unappreciated topological complexity in mTORC1 regulation. Interestingly, topological differences in mTORC1 regulation by the tumor suppressor proteins Lkb1 and Tsc1/Tsc2 may underlie their tissue specificity of tumor suppressor action.
Details
- Title: Subtitle
- Cell-type-dependent regulation of mTORC1 by REDD1 and the tumor suppressors TSC1/TSC2 and LKB1 in response to hypoxia
- Creators
- Nicholas C Wolff - University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9133, USASilvia Vega-Rubin-de-CelisXian-Jin XieDiego H CastrillonWareef KabbaniJames Brugarolas
- Resource Type
- Journal article
- Publication Details
- Molecular and cellular biology, Vol.31(9), pp.1870-1884
- Publisher
- United States
- DOI
- 10.1128/MCB.01393-10
- PMID
- 21383064
- PMCID
- PMC3133225
- ISSN
- 0270-7306
- eISSN
- 1098-5549
- Grant note
- K08 NS051843 / NINDS NIH HHS R01 CA129387 / NCI NIH HHS R01CA129387 / NCI NIH HHS R01 CA137181 / NCI NIH HHS K08NS051843 / NINDS NIH HHS
- Language
- English
- Date published
- 05/2011
- Academic Unit
- Preventive and Community Dentistry; Biostatistics; Dental Research
- Record Identifier
- 9983917681102771
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