Regulation of the HIF-1α Level Is Essential for Hematopoietic Stem Cells

Takubo, Keiyo; Goda, Nobuhito; Yamada, Wakako; Iriuchishima, Hirono; Ikeda, Eiji; Kubota, Yoshiaki; Shima, Haruko; Johnson, Randall S.; Hirao, Atsushi; Suematsu, Makoto; Suda, Toshio

doi:10.1016/j.stem.2010.06.020

Cited by 806 publications

(849 citation statements)

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“…HIF activation by hypoxic niches within bone marrow is critically important for controlling the fate of hematopoietic stem cells and their progeny, orchestrating a balance of quiescence, self-renewal, differentiation, and apoptosis (37,38). Because TACC3-/-embryos exhibit dramatically reduced hematopoietic stem cell colony formation activity (approximately 1-5% of WT) (30), we propose that loss of TACC3 may compromise HIF activity and regulation of hematopoietic stem cell fate.…”

Section: Mutations In Arnt Pas-b Perturb Coactivator Binding and Hifmentioning

confidence: 99%

Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B

Partch

Gardner

2011

Proc. Natl. Acad. Sci. U.S.A.

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Hypoxia-inducible factor (HIF) is the key transcriptional effector of the hypoxia response in eukaryotes, coordinating the expression of genes involved in oxygen transport, glycolysis, and angiogenesis to promote adaptation to low oxygen levels. HIF is a basic helixloop-helix (bHLH)-PAS (PER-ARNT-SIM) heterodimer composed of an oxygen-labile HIF-α subunit and a constitutively expressed aryl hydrocarbon receptor nuclear translocator (ARNT) subunit, which dimerize via basic helix-loop-helix and PAS domains, and recruit coactivators via HIF-α C-terminal transactivation domains. Here we demonstrate that the ARNT PAS-B domain provides an additional recruitment site by binding the coactivator transforming acidic coiled-coil 3 (TACC3) in a step necessary for transcriptional responses to hypoxia. Structural insights from NMR spectroscopy illustrate how this PAS domain simultaneously mediates interactions with HIF-α and TACC3. Finally, mutations on ARNT PAS-B modulate coactivator selectivity and target gene induction by HIF in vivo, demonstrating a bifunctional role for transcriptional regulation by PAS domains within bHLH-PAS transcription factors. transcriptional coactivators | protein/protein interactions | bifunctional interactionsA ryl hydrocarbon receptor nuclear translocator (ARNT) is the obligate heterodimeric partner for the basic helix-loop-helix (bHLH)-PAS (PER-ARNT-SIM) proteins aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor-α (HIF-α), which serve as environmental sensors for xenobiotics and hypoxia, respectively (1). bHLH-PAS heterodimers are dependent on intersubunit contacts between the basic bHLH and tandem PAS domains (2-4). The second of two PAS domains, PAS-B, plays a critical role in maintaining the stability of this complex, given that mutations in HIF-2α PAS-B disrupt HIF-α/ARNT interactions and decrease transactivation in vivo (3, 4). Therefore, our current model of bHLH-PAS heterodimer architecture is based on nucleation of the core transcription factor complex by bHLH and PAS domains, leaving C-terminal transactivation domains (TADs) to recruit coactivator proteins that are required for gene regulation (Fig. 1A).Further study of HIF TADs reveals that not all are essential for HIF function. In particular, deletion of the putative ARNT C-terminal TAD has a minimal effect on transactivation of endogenous targets (5-7), whereas deletion of the two HIF-α TADs (N-TAD and C-TAD) eliminates hypoxia-induced transactivation (8). Consequently, study of HIF transcriptional regulation has focused on the HIF-α TADs, identifying the C-TAD as the primary site of recruitment for p300/CBP (9) and the N-TAD as a determining factor in the distinctive profiles of target gene induction by . Selectivity is mediated in part by the recruitment of different coactivators by the N-TADs of the two HIF-α isoforms, building on an emerging theme that transcriptional coregulators and promoter context influence the specificity of gene induction by transcription factors (11,12). Domain-swapping studies have shown tha...

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Section: Mutations In Arnt Pas-b Perturb Coactivator Binding and Hifmentioning

confidence: 99%

Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B

Partch

Gardner

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Recently, Takubo et al (35) reported that normal hematopoietic stem cells (HSCs) maintain intracellular hypoxia and stabilize HIF-1␣ protein and that HSCs maintain cell cycle quiescence through the precise regulation of the HIF-1␣ level. It was also shown that HIF-1␣ plays a role in myeloid leukemic cell differentiation induced by hypoxia (14, 28, 36 -38) and that a clinically useful differentiation-inducing drug, all-trans retinoic acid, stabilizes HIF-1␣ protein (30).…”

Section: Ttgcaatmentioning

confidence: 99%

Synergistic Induction of Galectin-1 by CCAAT/Enhancer Binding Protein α and Hypoxia-inducible Factor 1α and Its Role in Differentiation of Acute Myeloid Leukemic Cells

Zhao

Jiang

et al. 2011

Journal of Biological Chemistry

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Background: Galectin-1 is a widely investigated cell surface glycoprotein-binding protein that mediates multiple cellular activities. Results: Galectin-1 is synergistically induced by C/EBP␣ and HIF-1␣ and facilitates the differentiation of leukemic cells. Conclusion: Galectin-1 is an important mediator for leukemic cell differentiation. Significance: Learning how galectin-1 expression is regulated by hematopoietic cell differentiation-associated transcriptional factors is of significance in understanding leukemic cell differentiation.

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“…This effect has been shown to be dependent on HIF-1α in multiple cell types, including various cancer cell lines (31)(32)(33)(34), fibroblasts (34), lymphocytes (34), and hematopoietic stem cells (35). Forced overexpression of HIF-1α is sufficient to arrest the mammalian cell cycle in G1 phase (31,36).…”

mentioning

confidence: 99%

Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression

Hubbi¹,

Gilkes

Hu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates adaptive responses to oxygen deprivation. In addition, the HIF-1α subunit has a nontranscriptional role as a negative regulator of DNA replication through effects on minichromosome maintenance helicase loading and activation. However, some cell types continue to replicate under hypoxic conditions. The mechanism by which these cells maintain proliferation in the presence of elevated HIF-1α levels is unclear. Here we report that HIF-1α physically and functionally interacts with cyclin-dependent kinase 1 (Cdk1) and Cdk2. Cdk1 activity blocks lysosomal degradation of HIF-1α and increases HIF-1α protein stability and transcriptional activity. By contrast, Cdk2 activity promotes lysosomal degradation of HIF-1α at the G1/S phase transition. Blocking lysosomal degradation by genetic or pharmacological means leads to HIF-1α-dependent cell-cycle arrest, demonstrating that lysosomal degradation of HIF-1α is an essential step for the maintenance of cell-cycle progression under hypoxic conditions. cell proliferation | chaperone mediated autophagy | lysosome

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Regulation of the HIF-1α Level Is Essential for Hematopoietic Stem Cells

Cited by 806 publications

References 40 publications

Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B

Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B

Synergistic Induction of Galectin-1 by CCAAT/Enhancer Binding Protein α and Hypoxia-inducible Factor 1α and Its Role in Differentiation of Acute Myeloid Leukemic Cells

Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression

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