Hypoxia-Inducible Factor 1 Regulation through Cross Talk between mTOR and MT1-MMP |
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| Authors: | Takeharu Sakamoto Jane S Weng Toshiro Hara Seiko Yoshino Hiroko Kozuka-Hata Masaaki Oyama Motoharu Seiki |
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| Institution: | aDivision of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan;bMedical Proteomics Laboratory, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan |
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| Abstract: | Hypoxia-inducible factor 1 (HIF-1) plays a key role in the cellular adaptation to hypoxia. Although HIF-1 is usually strongly suppressed by posttranslational mechanisms during normoxia, HIF-1 is active and enhances tumorigenicity in malignant tumor cells that express the membrane protease MT1-MMP. The cytoplasmic tail of MT1-MMP, which can bind a HIF-1 suppressor protein called factor inhibiting HIF-1 (FIH-1), promotes inhibition of FIH-1 by Mint3 during normoxia. To explore possible links between HIF-1 activation by MT1-MMP/Mint3 and tumor growth signals, we surveyed a panel of 252 signaling inhibitors. The mTOR inhibitor rapamycin was identified as a possible modulator, and it inhibited the mTOR-dependent phosphorylation of Mint3 that is required for FIH-1 inhibition. A mutant Mint3 protein that cannot be phosphorylated exhibited a reduced ability to inhibit FIH-1 and promoted tumor formation in mice. These data suggest a novel molecular link between the important hub proteins MT1-MMP and mTOR that contributes to tumor malignancy. |
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