Cell-Type-Dependent Regulation of mTORC1 by REDD1 and the Tumor Suppressors TSC1/TSC2 and LKB1 in Response to Hypoxia

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.

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Correction for Wolff et al., “Cell-Type-Dependent Regulation of mTORC1 by REDD1 and the Tumor Suppressors TSC1/TSC2 and LKB1 in Response to Hypoxia”

ACKNOWLEDGMENTS

We are grateful to A. Klippel for REDD1 polyclonal antibody, D. J. Kwiatkowski for Tsc1^F/F mice, F. J. Gonzalez for Arnt^F/F mice, N. Bardeesy for Lkb1^F/F mice, A. D. Nguyen and R. A. DeBose-Boyd for advice on hepatocyte processing and culture, and to members of the Brugarolas lab for discussions.

S.V.-R.-D.-C. was supported in part by a fellowship from Fundacion Caja Madrid. This work was supported by the following grants to J.B.: K08NS051843, RO1CA129387, Basil O'Connor scholar award (5FY06582), and a V scholar award. J.B. is a Virginia Murchison Linthicum Scholar in medical research at UT Southwestern.

The content is solely the responsibility of the authors and does not represent official views from any of the granting agencies. There are no conflicts of interest.