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Microtubule Disruption Utilizes an NFκB-dependent Pathway to Stabilize HIF-1α Protein

J. Biol. Chem., 28 February 2003
Vol. 278, Issue 9, p. 7445-7452
DOI: 10.1074/jbc.M209804200

Microtubule Disruption Utilizes an NFκB-dependent Pathway to Stabilize HIF-1α Protein

Abstract

Hypoxia-inducible factor (HIF)-1α levels are elevated in normoxic cells undergoing physiological processes involving large scale microtubule reorganization, such as embryonic development, wound healing, and tumor cell metastasis. Although alterations in microtubules affect numerous cellular responses, no data have yet implicated microtubule dynamics in HIF-1α regulation. To investigate the effect of microtubule change upon HIF-1α regulation, we treated cells with the microtubule-depolymerizing agents (MDAs) colchicine, vinblastine or nocodazole. We demonstrate that these agents are able to induce transcriptionally active HIF-1. MDA-mediated induction of HIF-1α required microtubule depolymerization, since HIF-1α levels were unchanged in cells treated with either the microtubule-stabilizing agent paclitaxel, or an inactive form of colchicine, or in colchicine-resistant cells. HIF-1 induction was dependent upon cellular transcription, as transcription inhibitors abrogated HIF-1α protein up-regulation. The ability of transcriptional inhibitors to interfere with HIF-1α accumulation was specific to the MDA-initiated pathway, as they were ineffective in preventing hypoxia-mediated HIF-1 induction, which occurs by a distinct post-translational pathway. Moreover, we provide evidence implicating a requirement for NFκB transcription in the HIF-1 induction mediated by MDAs. The ability of MDAs to induce HIF-1α is dependent upon activation of NFκB, since inhibition of NFκB either pharmacologically or by transfection of an NFκB super-repressor plasmid abrogated this induction. Collectively, these data support a model in which NFκB is a focal point for the convergence of MDA-mediated signaling events leading to HIF-1 induction, thus revealing a novel aspect of HIF-1α regulation and function.

  • Abbreviations:
    HIF-1
    hypoxia inducible factor-1
    MDA
    microtubule-depolymerizing agent
    vin
    vinblastine
    col
    colchicine
    noco
    nocodazole
    taxol
    paclitaxel
    AcD
    actinomycin-D
    DCB
    dichlorobenzimidazole riboside
    phe
    phenanthroline
    γ-lumicol
    γ-lumicolchicine
    NFκB
    nuclear factor κB
    NFRP
    NFκB super-repressor plasmid
    iNOS
    inducible nitric-oxide synthetase
    ARNT
    aryl hydrocarbon nuclear translocator
    HA
    hemagglutinin
    PDTC
    pyrrolidinedithiocarbamate
    CHX
    cycloheximide
    PI
    phosphatidylinositol
    CMV
    cytomegalovirus
    • Received September 24, 2002.
    • Revision received December 11, 2002.

    Citation:

    Y.-J. Jung, J. S. Isaacs, S. Lee, J. Trepel, and L. Neckers, Microtubule Disruption Utilizes an NFκB-dependent Pathway to Stabilize HIF-1α Protein. J. Biol. Chem. 278, 7445-7452 (2003).

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