Linked Life Data

12488445

Source:http://linkedlifedata.com/resource/pubmed/id/12488445

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pubmed-article:12488445pubmed:abstractTextHypoxia-inducible factor (HIF)-1alpha 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-1alpha regulation. To investigate the effect of microtubule change upon HIF-1alpha 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-1alpha required microtubule depolymerization, since HIF-1alpha 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-1alpha protein up-regulation. The ability of transcriptional inhibitors to interfere with HIF-1alpha 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 NFkappaB transcription in the HIF-1 induction mediated by MDAs. The ability of MDAs to induce HIF-1alpha is dependent upon activation of NFkappaB, since inhibition of NFkappaB either pharmacologically or by transfection of an NFkappaB super-repressor plasmid abrogated this induction. Collectively, these data support a model in which NFkappaB is a focal point for the convergence of MDA-mediated signaling events leading to HIF-1 induction, thus revealing a novel aspect of HIF-1alpha regulation and function.lld:pubmed
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pubmed-article:12488445pubmed:articleTitleMicrotubule disruption utilizes an NFkappa B-dependent pathway to stabilize HIF-1alpha protein.lld:pubmed
pubmed-article:12488445pubmed:affiliationCell and Cancer Biology Branch, Center for Cancer Research, NCI, National Institutes of Health, Rockville, Maryland 20850, USA.lld:pubmed
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