The N-Terminal Transactivation Domain Confers Target Gene Specificity of Hypoxia-inducible Factors HIF-1α and HIF-2α

Hu, Cheng-Jun; Sataur, Aneesa; Wang, Liyi; Chen, Hongqing; Simon, M. Celeste

doi:10.1091/mbc.e06-05-0419

Cited by 316 publications

(341 citation statements)

References 45 publications

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“…Another independent study confirmed this proposal. The authors showed that pgkI is a specific target of the N-TAD in the context of exogenous expression of truncated HIF-a constructs (Hu et al, 2007). Moreover, the N-TAD is essential to confer HIF-1 versus HIF-2 specificity of a given target (Hu et al, 2007), which consolidates our proposal of two non-redundant TADs.…”

Section: Discussionsupporting

confidence: 58%

“…The authors showed that pgkI is a specific target of the N-TAD in the context of exogenous expression of truncated HIF-a constructs (Hu et al, 2007). Moreover, the N-TAD is essential to confer HIF-1 versus HIF-2 specificity of a given target (Hu et al, 2007), which consolidates our proposal of two non-redundant TADs. Therefore, pharmacological inhibition of FIH, in renal cells constitutively expressing HIF-1a, led to specific induction of C-TAD genes, such as phd3 and vegf, but did not affect N-TAD genes, such as pgkI and bnip3 (Yan et al, 2007).…”

Section: Discussionsupporting

confidence: 58%

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The asparaginyl hydroxylase factor-inhibiting HIF is essential for tumor growth through suppression of the p53–p21 axis

et al. 2011

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We showed previously that factor-inhibiting hypoxiainducible factor HIF (FIH) monitors the expression of a spectrum of genes that are dictated by the cell's partial oxygen pressure. This action is mediated by the C-TAD, one of two transactivation domains (TADs) of the hypoxia-inducible factor. Here, we questioned: (1) the function of FIH as a HIF-1 modulator of gene expression in the context of a physiological oxygen gradient occurring in three-dimensional cultures and in tumors and (2) the role of FIH as a modulator of the growth of human tumor cells. We first showed that the expression pattern of HIF target genes that depend on the C-TAD, such as carbonic anhydrase IX, was spacially displaced to more oxygenated areas when FIH was silenced, whereas overexpression of FIH restricted this pattern to more hypoxic areas. Second, we showed that silencing fih severely reduced in vitro cell proliferation and in vivo tumor growth of LS174 colon adenocarcinoma and A375 melanoma cells. Finally, silencing of fih significantly increased both the total and phosphorylated forms of the tumor suppressor p53, leading to an increase in its direct target, the cell cycle inhibitor p21. Moreover, p53-deficient or mutant cells were totally insensitive to FIH expression. Thus, FIH activity is essential for tumor growth through the suppression of the p53-p21 axis, the major barrier that prevents cancer progression.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionsupporting

confidence: 58%

The asparaginyl hydroxylase factor-inhibiting HIF is essential for tumor growth through suppression of the p53–p21 axis

et al. 2011

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“…23 HIF-1a/HIF-2a chimeric proteins, where innate NAD and/or CAD domains of each paralogue were 'swapped', were used to investigate the effect of each on the transcription of endogenous HIF target genes deemed to be either HIF-1a specific, common targets of both HIF-1a and HIF-2a, or HIF-2a specific. Interestingly, swapping the CAD between HIF-1a and HIF-2a had no effect on the target transcripts measured, whereas substitution of both the NAD and the CAD effectively caused HIF-1a to behave as HIF-2a, and vice versa.…”

Section: Hif Transactivation Domainsmentioning

confidence: 99%

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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“…Target gene specificity in this case likely arises from additional trans-acting factors and/or cis-regulatory elements that cooperate specifically with HIF-2a. In a variety of HIF-2a-selective promoters (including the WISP2 promoter) HREs have previously been reported to cooperate with ETS-family transcription factor-binding sites (Elvert et al, 2003;Aprelikova et al, 2006;Hu et al, 2007;Le Bras et al, 2007;Wang et al, 2010), and HIF-2a has been shown to physically interact with ETS-1 and ELK-1 (Elvert et al, 2003;Aprelikova et al, 2006). Other HIF-2a-regulated genes at least contained one consensus HRE (Covello et al, 2006;Yamashita et al, 2008;Yang et al, 2010), although the stringency with which the core HRE has been determined was sometimes lowered to only half-sites of the 5 0 -RCGTG-3 0 motif (Saito et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

et al. 2011

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Tumor progression is intrinsically tied to the clonal selection of tumor cells with acquired phenotypes allowing to cope with a hostile microenvironment. Hypoxiainducible factors (HIFs) master the transcriptional response to local tissue hypoxia, a hallmark of solid tumors. Here, we report significantly longer patient survival in breast cancer with high levels of HIF-2a. Amphiregulin (AREG) and WNT1-inducible signaling pathway protein-2 (WISP2) expression was strongly HIF2a-dependent and their promoters were particularly responsive to HIF-2a. The endogenous AREG promoter recruited HIF-2a in the absence of a classical HIF-DNA interaction motif, revealing a novel mechanism of gene regulation. Loss of AREG expression in HIF-2a-depleted cells was accompanied by reduced activation of epidermal growth factor (EGF) receptor family members. Apparently opposing results from patient and in vitro data point to an HIF-2a-dependent auto-stimulatory tumor phenotype that, while promoting EGF signaling in cellular models, increased the survival of diagnosed and treated human patients. Our findings suggest a model where HIF2a-mediated autocrine growth signaling in breast cancer sustains a state of cellular self-sufficiency, thereby masking unfavorable microenvironmental growth conditions, limiting adverse selection and improving therapy efficacy. Importantly, HIF-2a/AREG/WISP2-expressing tumors were associated with luminal tumor differentiation, indicative of a better response to classical treatments. Shifting the HIF-1/2a balance toward an HIF-2-dominated phenotype could thus offer a novel approach in breast cancer therapy.

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The N-Terminal Transactivation Domain Confers Target Gene Specificity of Hypoxia-inducible Factors HIF-1α and HIF-2α

Cited by 316 publications

References 45 publications

The asparaginyl hydroxylase factor-inhibiting HIF is essential for tumor growth through suppression of the p53–p21 axis

The asparaginyl hydroxylase factor-inhibiting HIF is essential for tumor growth through suppression of the p53–p21 axis

Turn me on: regulating HIF transcriptional activity

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

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