title: Hypoxia-inducible factor 1 regulation through cross talk between mTOR and MT1-MMP.
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.
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
authors.forename: Takeharu
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Jane S
authors.initials: JS
authors.lastname: Weng
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
authors.forename: Seiko
authors.initials: S
authors.lastname: Yoshino
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kozuka-Hata
authors.forename: Masaaki
authors.initials: M
authors.lastname: Oyama
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: C117536:APBA3 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D002227:Carbazoles; D002352:Carrier Proteins; D051793:Hypoxia-Inducible Factor 1; D047428:Protein Kinase Inhibitors; D012097:Repressor Proteins; C073601:KT 5823; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D020123:Sirolimus