Mol Cell Biol 2011,
PMID: 21383064
Wolff, Nicholas C; Vega-Rubin-de-Celis, Silvia; Xie, Xian-Jin; Castrillon, Diego H; Kabbani, Wareef; Brugarolas, James
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.
Diseases/Pathways annotated by Medline MESH: Anoxia
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Text Mining Data
mTORC1 — REDD1: "
Cell-type dependent
regulation of
mTORC1 by
REDD1 and the tumor suppressors TSC1/TSC2 and LKB1 in response to hypoxia
"
mTORC1 → Tsc1/Tsc2 complex: "
We previously reported that mTORC1 regulation by hypoxia involves Redd1 and the Tsc1/Tsc2 complex
"
mTORC1 → Redd1: "
We previously reported that mTORC1 regulation by hypoxia involves Redd1 and the Tsc1/Tsc2 complex
"
mTORC1 ⊣ raptor: "
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
"
mTORC1 ⊣ AMPK: "
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
"
raptor → AMPK: "
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
"
AMPK → raptor: "
In liver cells, raptor phosphorylation is essential for both AMPK and hypoxia signaling
"
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