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See detailTransduction pathways involved in Hypoxia-Inducible Factor-1 phosphorylation and activation.
Minet, E.; Michel, G.; Mottet, Denis ULg et al

in Free Radical Biology & Medicine (2001), 31(7), 847-55

Hypoxia-Inducible Factor-1 (HIF-1) is a transcription factor which is activated by hypoxia and involved in the adaptative response of the cell to oxygen deprivation. During hypoxic stress, HIF-1 triggers ... [more ▼]

Hypoxia-Inducible Factor-1 (HIF-1) is a transcription factor which is activated by hypoxia and involved in the adaptative response of the cell to oxygen deprivation. During hypoxic stress, HIF-1 triggers the overexpression of genes coding for glycolytic enzymes and angiogenic factors. To be active HIF-1 must be phosphorylated. HIF-1 is a substrate for various kinase pathways including PI-3K and the MAP kinases ERK and p38. Several transduction pathways have been proposed which act downstream of putative oxygen sensors and lead to the activation of these kinases. In this review, we summarize some of the latest advances describing the possible signaling pathways leading to HIF-1 phosphorylation and subsequent activation. The physiological relevance of these regulations is also discussed. [less ▲]

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See detailc-JUN gene induction and AP-1 activity is regulated by a JNK-dependent pathway in hypoxic HepG2 cells.
Minet, E.; Michel, G.; Mottet, Denis ULg et al

in Experimental Cell Research (2001), 265(1), 114-24

Hypoxia is an important pathophysiological stress that occurs during blood vessel injuries and tumor growth. It is now well documented that hypoxia leads to the activation of several transcription factors ... [more ▼]

Hypoxia is an important pathophysiological stress that occurs during blood vessel injuries and tumor growth. It is now well documented that hypoxia leads to the activation of several transcription factors which participate in the adaptive response of the cells to hypoxia. Among these transcription factors, AP-1 is rapidly activated by hypoxia and triggers bFGF, VEGF, and tyrosine hydroxylase gene expression. However, the mechanisms of AP-1 activation by hypoxia are not well understood. In this report, we studied the events leading to AP-1 activation in hypoxia. We found that c-jun protein accumulates in hypoxic HepG2 cells. This overexpression is concomitant with c-jun phosphorylation and JNK activation. Moreover, we showed that AP-1 is transcriptionally active. We also observed that AP-1 transcriptional activity is inhibited by a MEKK1 dominant negative mutant. Moreover, the MEKK1 dominant negative mutant as well as deletion of the AP-1 binding sites within the c-jun promoter inhibited the c-jun promoter activation by hypoxia. All together, these results indicate that, in hypoxic HepG2 cells, AP-1 is activated through a JNK-dependent pathway and that it is involved in the regulation of the c-jun promoter, inducing a positive feedback loop on AP-1 activation via c-jun overexpression. [less ▲]

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See detailHIF-1 and AP-1 cooperate to increase gene expression in hypoxia: role of MAP kinases.
Michiels, C.; Minet, E.; Michel, G. et al

in IUBMB Life (2001), 52(1-2), 49-53

HIF-1 is the main transcription factor responsible for increased gene expression in hypoxia: VEGF, erythropoietin, GLUT-1, and glycolytic enzymes are such target genes and all participate in the ... [more ▼]

HIF-1 is the main transcription factor responsible for increased gene expression in hypoxia: VEGF, erythropoietin, GLUT-1, and glycolytic enzymes are such target genes and all participate in the adaptative response of cells to hypoxia. AP-1 activation by hypoxia has also been demonstrated in several cell lines and it cooperates with HIF-1 for increasing VEGF gene transcription in hypoxia. Both HIF-1 and AP-1 activation by hypoxia seems to involve members of the MAP kinase family. Here, we summarize the data indicating that ERK and JNK are needed for activation of HIF-1 and AP-1, respectively. [less ▲]

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See detailERK activation upon hypoxia: involvement in HIF-1 activation.
Minet, E.; Arnould, T.; Michel, G. et al

in FEBS Letters (2000), 468(1), 53-8

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor activated by hypoxia. The HIF-1 activation transduction pathway is poorly understood. In this report, we investigated the activation of ... [more ▼]

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor activated by hypoxia. The HIF-1 activation transduction pathway is poorly understood. In this report, we investigated the activation of extracellular regulated kinases (ERK) in hypoxia and their involvement in HIF-1 activation. We demonstrated that in human microvascular endothelial cells-1 (HMEC-1), ERK kinases are activated during hypoxia. Using dominant negative mutants, we showed that ERK1 is needed for hypoxia-induced HIF-1 transactivation activity. Moreover, using a kinase assay and Western blot experiments, we showed that HIF-1alpha is phosphorylated in hypoxia by an ERK-dependent pathway. These results evidence the role of mitogen-activated protein kinase in the transcriptional response to hypoxia. [less ▲]

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See detailHypoxia-induced activation of HIF-1: role of HIF-1alpha-Hsp90 interaction.
Minet, E.; Mottet, Denis ULg; Michel, G. et al

in FEBS Letters (1999), 460(2), 251-6

The protein chaperone heat shock protein 90 (Hsp90) is a major regulator of different transcription factors such as MyoD, a basic helix loop helix (bHLH) protein, and the bHLH-Per-aryl hydrocarbon nuclear ... [more ▼]

The protein chaperone heat shock protein 90 (Hsp90) is a major regulator of different transcription factors such as MyoD, a basic helix loop helix (bHLH) protein, and the bHLH-Per-aryl hydrocarbon nuclear translocator (ARNT)-Sim (PAS) factors Sim and aryl hydrocarbon receptor (Ahr). The transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), involved in the response to hypoxia, also belongs to the bHLH-PAS family. This work was aimed to investigate the putative role of Hsp90 in HIF-1 activation by hypoxia. Using a EGFP-HIF-1alpha fusion protein, co-immunoprecipitation experiments evidenced that the chimeric protein expressed in COS-7 cells interacts with Hsp90 in normoxia but not in hypoxia. We also demonstrated that Hsp90 interacts with the bHLH-PAS domain of HIF-1alpha. Moreover, Hsp90 is not co-translocated with HIF-1alpha into the nucleus. At last, we showed that Hsp90 activity is essential for HIF-1 activation in hypoxia since it is inhibited in the presence of geldanamycin. These results indicate that Hsp90 is a major regulator in HIF-1alpha activation. [less ▲]

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