Hypoxia Requires Notch Signaling to Maintain the Undifferentiated Cell State

Gustafsson, Maria; Zheng, Xiaowei; Pereira, Teresa; Gradin, Katarina; Jin, Shaobo; Lundkvist, Johan; Ruas, Jorge L.; Poellinger, Lorenz; Lendahl, Urban; Bondesson, Maria

doi:10.1016/j.devcel.2005.09.010

Cited by 985 publications

(974 citation statements)

References 52 publications

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“…66 Conversely, the HIF proteins can also participate in transcriptional regulation of non-canonical pathways such as Myc and Notch signalling, where they are recruited to DNA via interaction with other transcription factors. 67 Finally, Hsp90 has been shown in a number of studies to be required for HIF activity, although this appears to be predominantly through regulation of HIF stability as described previously. 68 …”

Section: Other Modifications Affecting Hif-driven Transcriptionmentioning

confidence: 83%

Turn me on: regulating HIF transcriptional activity

2008

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The hypoxia-inducible factors (HIFs) are critical for cellular adaptation to limiting oxygen and regulate a wide array of genes when cued by cellular oxygen-sensing mechanisms. HIF is able to direct transcription from either of two transactivation domains, each of which is regulated by distinct mechanisms. The oxygen-dependent asparaginyl hydroxylase factor-inhibiting HIF-1a (FIH-1) is a key regulator of the HIF C-terminal transactivation domain, and provides a direct link between oxygen sensation and HIFmediated transcription. Additionally, there are phosphorylation and nitrosylation events reported to modulate HIF transcriptional activity, as well as numerous transcriptional coactivators and other interacting proteins that together provide cell and tissue specificity of HIF target gene regulation. The maintenance of oxygen homeostasis is a crucial physiological requirement that involves coordinated regulation of a plethora of genes. The hypoxia-inducible transcription factors (HIFs) are responsible for a major genomic response to hypoxia, where cellular oxygen demand exceeds supply. The HIFs directly regulate the transcription of more than 70 genes involved in cellular processes that act to directly address this deficit by decreasing oxygen dependence and consumption by cells, and by increasing the efficiency of oxygen delivery to cells. These processes include vasculogenesis and angiogenesis, metabolism, vasodilation, cell migration, signalling and cell fate decisions. As such, the HIFs are fundamental to embryonic development and the pathophysiology of many serious human diseases, and are therefore subject to strict regulatory mechanisms that act to limit transcriptional activity to periods of cellular oxygen stress. The HIF proteins are subject to oxygen-dependent regulation, both at the level of protein stability (reviewed in this issue by R Bruick) and transcriptional activity, rendering them almost inactive at normoxia, but potently inducible in hypoxia. The regulation of the transcriptional activity of the HIF proteins, both via oxygen-dependent and oxygen-independent mechanisms, will be discussed in this review. The HIFsHIF is assembled from a-and b-subunits to become a transcriptionally active heterodimer. 1 Both subunits are members of the bHLH/PAS (basic helix-loop-helix/Per-ArntSim homology) family of transcription factors, and both contain transactivation domains (Figure 1). 2,3 Whereas HIF1b, also known as the aryl hydrocarbon receptor nuclear translocator (Arnt1), is a constitutively expressed nuclear protein, the a-subunit is strictly regulated in an oxygendependent manner. There are three paralogues of the HIF-a subunit, HIF-1a, HIF-2a and HIF-3a, and three paralogues of HIF-1b (Arnt1, Arnt2 and Arnt3), with either HIF-1a or HIF-2a being able to heterodimerize with HIF-1b to form the functional HIF transcription factor complexes responsible for the hypoxic shift in gene expression. HIF-3a has no known role as an active transcription factor, and is instead postulated to behave as a negative reg...

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Section: Other Modifications Affecting Hif-driven Transcriptionmentioning

confidence: 83%

Turn me on: regulating HIF transcriptional activity

2008

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“…Hes1 levels are also elevated by hypoxia mimetics that stabilize HIF-1α. These results imply that HIF-1α directly mediates the hypoxic effects on Notch activity; indeed, HIF-1α has been shown to physically associate with Notch ICD, promoting its stability 72 . The authors propose a model in which HIF-1α interacts with Notch-CSL transcriptional complexes at Notch-responsive promoters in hypoxic cells to control the differentiation status of myogenic and neuronal precursors (see Figure 4A).…”

Section: Hifs Affect Stem and Progenitor Cell Differentiationmentioning

confidence: 85%

“…Haemangioblast proliferation within embryoid bodies is enhanced by hypoxia, which implies that the vascular and haematopoietic defects seen in HIF-deficient embryos are partly the result of depletion of a common progenitor pool. 72 . Hypoxia (1% O 2 ), via the accumulation of HIF-1α, blocks the myogenic differentiation of C2C12 myoblast cells and the neuronal differentiation of P19 embryonic carcinoma cells.…”

Section: Hifs Affect Stem and Progenitor Cell Differentiationmentioning

confidence: 99%

The role of oxygen availability in embryonic development and stem cell function

Simon¹,

Keith²

2008

Nat Rev Mol Cell Biol

819

767

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Low levels of oxygen (O 2 ) occur naturally in developing embryos. Cells respond to their hypoxic microenvironment by stimulating several hypoxia-inducible factors (and other molecules that mediate O 2 homeostasis), which then coordinate the development of the blood, vasculature, placenta, nervous system, and other organs. Furthermore, embryonic stem and progenitor cells frequently occupy hypoxic 'niches' and low O 2 regulates their differentiation. Recent work has revealed an important link between factors involved in regulating stem/progenitor cell behaviour and hypoxiainducible factors, which provides a molecular framework for hypoxic control of differentiation and cell fate. These findings have important implications for the development of therapies for tissue regeneration and disease.

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“…The role of oxygen tension on cellular differentiation is not restricted to the hematopoietic system (Kroon et al, 2001;Li et al, 2002;Gustafsson et al, 2005). Interestingly, several known hypoxia-activated genes, such as those encoding proteins involved in glucose metabolism like Glut1, are also regulated by growth factor signaling and by notch signaling, indicating a crosstalk between those pathways (Zelzer et al, 1998;Vander Heiden et al, 2001;Fukuda et al, 2002;Ciofani and Zuniga-Pflucker, 2005).…”

Section: Discussionmentioning

confidence: 99%

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

et al. 2006

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The transcription factor hypoxia inducible factor 1 (HIF1), an HIF1a-aryl hydrocarbon receptor nuclear translocator (ARNT) dimeric factor, is essential to the cellular response to hypoxia. We described a t(1;12)(q21;p13) chromosomal translocation in human acute myeloblastic leukemia that involves the translocated Ets leukemia (TEL/ETV6) and the ARNT genes and results in the expression of a TEL-ARNT fusion protein.Functional studies show that TEL-ARNT interacts with HIF1a and the complex binds to consensus hypoxia response element. In low oxygen tension conditions, the HIF1a/TEL-ARNT complex does not activate transcription but exerts a dominant-negative effect on normal HIF1 activity. Differentiation of normal human CD34 þ progenitors cells along all the erythrocytic, megakaryocytic and granulocytic pathways was accelerated in low versus high oxygen tension conditions. Murine 32Dcl3 myeloid cells also show accelerated granulocytic differentiation in low oxygen tension in response to granulocyte colony-stimulating factor. Interestingly, stable expression of the TEL-ARNT in 32Dcl3 subclones resulted in impaired HIF1-mediated transcriptional response and inhibition of differentiation enhancement in hypoxic conditions. Taken together, our results underscore the role of oxygen tension in the modulation of normal hematopoietic differentiation, whose targeting can participate in human malignancies.

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Hypoxia Requires Notch Signaling to Maintain the Undifferentiated Cell State

Cited by 985 publications

References 52 publications

Turn me on: regulating HIF transcriptional activity

Turn me on: regulating HIF transcriptional activity

The role of oxygen availability in embryonic development and stem cell function

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

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