Hypoxia-inducible factor 1α is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif

Stephen C. Land, Andrew R. Tee

    Research output: Contribution to journalArticle

    308 Citations (Scopus)

    Abstract

    Tumors that form as a result of heightened mammalian target of rapamycin (mTOR) signaling are highly vascularized. This process of angiogenesis is regulated through hypoxia-inducible factor (HIF)-mediated transcription of angiogenic factors. It is recognized that inhibition of mTOR with rapamycin can diminish the process of angiogenesis. Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression potently enhances the activity of HIF1a and vascular endothelial growth factor (VEGF)-A secretion during hypoxia, which is reversed with rapamycin. Mutants of Rheb, which do not bind guanine nucleotide (D60K, D60V, N119I, and D122N) and are unable to activate mTOR, inhibit the activity of HIF when overexpressed. We show that regulatory associated protein of mTOR (Raptor) interacts with HIF1a and requires an mTOR signaling (TOS) motif located in the N terminus of HIF1a. Furthermore, a mutant of HIF1a lacking this TOS motif dominantly impaired HIF activity during hypoxia and was unable to bind to the co-activator CBP/p300. Rapamycin treatments do not affect the stability of HIF1a and modulate HIF activity via a Von Hippel-Lindau (VHL)-independent mechanism. We demonstrate that the high levels of HIF activity in cells devoid of TSC2 can be reversed by treatments with rapamycin or the readdition of TSC2. Our work explains why human cancers with aberrant mTOR signaling are prone to angiogenesis and suggests that inhibition of mTOR with rapamycin might be a suitable therapeutic strategy.
    Original languageEnglish
    Pages (from-to)20534-20543
    Number of pages10
    JournalJournal of Biological Chemistry
    Volume282
    Issue number28
    DOIs
    Publication statusPublished - Jul 2007

    Fingerprint

    Hypoxia-Inducible Factor 1
    Sirolimus
    Brain
    TOR Serine-Threonine Kinases
    Guanine Nucleotides
    Angiogenesis Inducing Agents
    Transcription factors
    Hypoxia
    Vascular Endothelial Growth Factor A
    Neoplasms
    Transcription Factors
    Tumors

    Keywords

    • Hypoxia-inducible factors
    • Angiogenic factors
    • Coactivators
    • Proteins
    • Mammalian target of rapamycin (mTOR)
    • mTOR
    • Signal transduction

    Cite this

    @article{ef77630f44b9496faf36925e539bac88,
    title = "Hypoxia-inducible factor 1α is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif",
    abstract = "Tumors that form as a result of heightened mammalian target of rapamycin (mTOR) signaling are highly vascularized. This process of angiogenesis is regulated through hypoxia-inducible factor (HIF)-mediated transcription of angiogenic factors. It is recognized that inhibition of mTOR with rapamycin can diminish the process of angiogenesis. Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression potently enhances the activity of HIF1a and vascular endothelial growth factor (VEGF)-A secretion during hypoxia, which is reversed with rapamycin. Mutants of Rheb, which do not bind guanine nucleotide (D60K, D60V, N119I, and D122N) and are unable to activate mTOR, inhibit the activity of HIF when overexpressed. We show that regulatory associated protein of mTOR (Raptor) interacts with HIF1a and requires an mTOR signaling (TOS) motif located in the N terminus of HIF1a. Furthermore, a mutant of HIF1a lacking this TOS motif dominantly impaired HIF activity during hypoxia and was unable to bind to the co-activator CBP/p300. Rapamycin treatments do not affect the stability of HIF1a and modulate HIF activity via a Von Hippel-Lindau (VHL)-independent mechanism. We demonstrate that the high levels of HIF activity in cells devoid of TSC2 can be reversed by treatments with rapamycin or the readdition of TSC2. Our work explains why human cancers with aberrant mTOR signaling are prone to angiogenesis and suggests that inhibition of mTOR with rapamycin might be a suitable therapeutic strategy.",
    keywords = "Hypoxia-inducible factors, Angiogenic factors, Coactivators, Proteins, Mammalian target of rapamycin (mTOR), mTOR, Signal transduction",
    author = "Land, {Stephen C.} and Tee, {Andrew R.}",
    note = "dc.publisher: American Society for Biochemistry and Molecular Biology The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. dc.description.sponsorship: British Heart Foundation Intermediate Research Fellowship FS/04/022 Association of International Cancer Research Career Development Fellowship 06-914/915 Tenovus",
    year = "2007",
    month = "7",
    doi = "10.1074/jbc.M611782200",
    language = "English",
    volume = "282",
    pages = "20534--20543",
    journal = "Journal of Biological Chemistry",
    issn = "0021-9258",
    publisher = "American Society for Biochemistry and Molecular Biology",
    number = "28",

    }

    Hypoxia-inducible factor 1α is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. / Land, Stephen C.; Tee, Andrew R.

    In: Journal of Biological Chemistry, Vol. 282, No. 28, 07.2007, p. 20534-20543.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Hypoxia-inducible factor 1α is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif

    AU - Land, Stephen C.

    AU - Tee, Andrew R.

    N1 - dc.publisher: American Society for Biochemistry and Molecular Biology The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. dc.description.sponsorship: British Heart Foundation Intermediate Research Fellowship FS/04/022 Association of International Cancer Research Career Development Fellowship 06-914/915 Tenovus

    PY - 2007/7

    Y1 - 2007/7

    N2 - Tumors that form as a result of heightened mammalian target of rapamycin (mTOR) signaling are highly vascularized. This process of angiogenesis is regulated through hypoxia-inducible factor (HIF)-mediated transcription of angiogenic factors. It is recognized that inhibition of mTOR with rapamycin can diminish the process of angiogenesis. Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression potently enhances the activity of HIF1a and vascular endothelial growth factor (VEGF)-A secretion during hypoxia, which is reversed with rapamycin. Mutants of Rheb, which do not bind guanine nucleotide (D60K, D60V, N119I, and D122N) and are unable to activate mTOR, inhibit the activity of HIF when overexpressed. We show that regulatory associated protein of mTOR (Raptor) interacts with HIF1a and requires an mTOR signaling (TOS) motif located in the N terminus of HIF1a. Furthermore, a mutant of HIF1a lacking this TOS motif dominantly impaired HIF activity during hypoxia and was unable to bind to the co-activator CBP/p300. Rapamycin treatments do not affect the stability of HIF1a and modulate HIF activity via a Von Hippel-Lindau (VHL)-independent mechanism. We demonstrate that the high levels of HIF activity in cells devoid of TSC2 can be reversed by treatments with rapamycin or the readdition of TSC2. Our work explains why human cancers with aberrant mTOR signaling are prone to angiogenesis and suggests that inhibition of mTOR with rapamycin might be a suitable therapeutic strategy.

    AB - Tumors that form as a result of heightened mammalian target of rapamycin (mTOR) signaling are highly vascularized. This process of angiogenesis is regulated through hypoxia-inducible factor (HIF)-mediated transcription of angiogenic factors. It is recognized that inhibition of mTOR with rapamycin can diminish the process of angiogenesis. Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression potently enhances the activity of HIF1a and vascular endothelial growth factor (VEGF)-A secretion during hypoxia, which is reversed with rapamycin. Mutants of Rheb, which do not bind guanine nucleotide (D60K, D60V, N119I, and D122N) and are unable to activate mTOR, inhibit the activity of HIF when overexpressed. We show that regulatory associated protein of mTOR (Raptor) interacts with HIF1a and requires an mTOR signaling (TOS) motif located in the N terminus of HIF1a. Furthermore, a mutant of HIF1a lacking this TOS motif dominantly impaired HIF activity during hypoxia and was unable to bind to the co-activator CBP/p300. Rapamycin treatments do not affect the stability of HIF1a and modulate HIF activity via a Von Hippel-Lindau (VHL)-independent mechanism. We demonstrate that the high levels of HIF activity in cells devoid of TSC2 can be reversed by treatments with rapamycin or the readdition of TSC2. Our work explains why human cancers with aberrant mTOR signaling are prone to angiogenesis and suggests that inhibition of mTOR with rapamycin might be a suitable therapeutic strategy.

    KW - Hypoxia-inducible factors

    KW - Angiogenic factors

    KW - Coactivators

    KW - Proteins

    KW - Mammalian target of rapamycin (mTOR)

    KW - mTOR

    KW - Signal transduction

    U2 - 10.1074/jbc.M611782200

    DO - 10.1074/jbc.M611782200

    M3 - Article

    VL - 282

    SP - 20534

    EP - 20543

    JO - Journal of Biological Chemistry

    JF - Journal of Biological Chemistry

    SN - 0021-9258

    IS - 28

    ER -