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SEPT9_i1 is required for the association between HIF-1? and importin-? to promote efficient nuclear translocation.

ABSTRACT: Septin 9 isoform 1 (SEPT9_i1) protein associates with hypoxia-inducible factor (HIF)-1? to augment HIF-1 transcriptional activity. The first 25 amino acids of SEPT9_i1 (N 25) are unique compared with other members of the mammalian septin family. This N 25 domain is critical for HIF-1 activation by SEPT9_i1 but not essential for the protein-protein interaction. Here, we show that expression of N 25 induces a significant dose-dependent inhibition of HIF-1 transcriptional activity under normoxia and hypoxia without influencing cellular HIF-1? protein levels. In vivo, N 25 expression inhibits proliferation, tumor growth and angiogenesis concomitant with decreased expression levels of intratumoral HIF-1 downstream genes. Depletion of endogenous SEPT9_i1 or the exogenous expression of N 25 fragment reduces nuclear HIF-1? levels accompanied by reciprocal accumulation of HIF-1? in the cytoplasm. Mechanistically, SEPT9_i1 binds to importin-? through N 25 depending on its bipartite nuclear localization signal, to scaffold the association between HIF-1? and importin-?, which leads to facilitating HIF-1? nuclear translocation. Our data explore a new and a previously unrecognized role of a septin protein in the cytoplasmic-nuclear translocation process. This new level in the regulation of HIF-1? translocation is critical for efficient HIF-1 transcriptional activation that could be targeted for cancer therapeutics.

SUBMITTER: Golan M

PROVIDER: S-EPMC3755080 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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SEPT9_i1 is required for the association between HIF-1α and importin-α to promote efficient nuclear translocation.

Golan Maya M Mabjeesh Nicola J NJ

Cell cycle (Georgetown, Tex.) 20130701 14

Septin 9 isoform 1 (SEPT9_i1) protein associates with hypoxia-inducible factor (HIF)-1α to augment HIF-1 transcriptional activity. The first 25 amino acids of SEPT9_i1 (N 25) are unique compared with other members of the mammalian septin family. This N 25 domain is critical for HIF-1 activation by SEPT9_i1 but not essential for the protein-protein interaction. Here, we show that expression of N 25 induces a significant dose-dependent inhibition of HIF-1 transcriptional activity under normoxia an ...[more]

PMID: 24067372

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Project description:BackgroundHypoxia-inducible factor (HIF)-1 is involved in the regulation of hypoxic preconditioning in cardiomyocytes. Under hypoxic conditions, HIF-1α accumulates and is translocated to the nucleus, where it forms an active complex with HIF-1β and activates transcription of approximately 60 kinds of hypoxia-adaptive genes. Microtubules are hollow tubular structures in the cell that maintain cellular morphology and that transport substances. This study attempted to clarify the role of microtubule structure in the endonuclear aggregation of HIF-1α following hypoxic preconditioning of cardiomyocytes.MethodsPrimary rat cardiomyocytes were isolated and cultured. The cardiomyocyte culture system was used to establish a hypoxia model and a hypoxic preconditioning model. Interventions were performed on primary cardiomyocytes using a microtubule-depolymerizing agent and different concentrations of a microtubule stabilizer. The microtubule structure and the degree of HIF-1α nuclear aggregation were observed by confocal laser scanning microscopy. The expression of HIF-1α in the cytoplasm and nucleus was detected using Western blotting. Cardiomyocyte energy content, reflected by adenosine triphosphate/adenosine diphosphate (ATP/ADP), and key glycolytic enzymes were monitored by colorimetry and high-performance liquid chromatography (HPLC). Reactive oxygen species (ROS) production was also used to comprehensively assess whether microtubule stabilization can enhance the myocardial protective effect of hypoxic preconditioning.ResultsDuring prolonged hypoxia, it was found that the destruction of the microtubule network structure of cardiomyocytes was gradually aggravated. After this preconditioning, an abundance of HIF-1α was clustered in the nucleus. When the microtubules were depolymerized and hypoxia pretreatment was performed, HIF-1α clustering occurred around the nucleus, and HIF-1α nuclear expression was low. The levels of key glycolytic enzymes were significantly higher in the microtubule stabilizer group than in the hypoxia group. Additionally, the levels of lactate dehydrogenase and ROS were significantly lower in the microtubule stabilizer group than in the hypoxia group.ConclusionThe microtubules of cardiomyocytes may be involved in the process of HIF-1α endonuclear aggregation, helping to enhance the anti-hypoxic ability of cardiomyocytes.

Dataset Information

SEPT9_i1 is required for the association between HIF-1? and importin-? to promote efficient nuclear translocation.

Publications

SEPT9_i1 is required for the association between HIF-1α and importin-α to promote efficient nuclear translocation.

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