Hypoxia-Induced Gene Expression Occurs Solely through the Action of Hypoxia-Inducible Factor 1α (HIF-1α): Role of Cytoplasmic Trapping of HIF-2α

Park, Sang-ki; Dadak, Agnes; Haase, Volker H.; Fontana, Lucrezia; Giaccia, Amato J.; Johnson, Randall S.

doi:10.1128/mcb.23.14.4959-4971.2003

Cited by 163 publications

(146 citation statements)

References 47 publications

(70 reference statements)

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“…These cell lines were either only immortalized by SV40 large T (MEF-Hif1a -/-T) or immortalized and transformed by H-ras (MEF-Hif1a -/-r T), respectively (Feldser et al , 1999 ;Ryan et al , 2000 ). Importantly, these MEF cell lines were shown to lack functional HIF-2 α protein (Park et al , 2003 ). Confirming the results obtained with HEK293 cells, γ H2AX levels in wt MEFs accumulated after 24 h exposure to 0.2 % O 2 but were strongly impaired in MEFs devoid of HIF-1 α .…”

Section: Hypoxic γ H2ax Accumulation Is Hif Dependentsupporting

confidence: 73%

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia

Wrann

Kaufmann²,

Wirthner³

et al. 2013

Biological Chemistry

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Abstract:The histone variant 2AX (H2AX) is phosphorylated at Serine 139 by the PI3K-like kinase family members ATM, ATR and DNA-PK. Genotoxic stress, such as tumor radioand chemotherapy, is considered to be the main inducer of phosphorylated H2AX ( γ H2AX), which forms distinct foci at sites of DNA damage where DNA repair factors accumulate. γ H2AX accumulation under severe hypoxic/anoxic (0.02 % oxygen) conditions has recently been reported to follow replication fork stalling in the absence of detectable DNA damage. In this study, we found HIF-dependent accumulation of γ H2AX in several cancer cell lines and mouse embryonic fibroblasts exposed to physiologically relevant chronic hypoxia (0.2 % oxygen), which did not induce detectable levels of DNA strand breaks. The hypoxic accumulation of γ H2AX was delayed by the RNAi-mediated knockdown of HIF-1 α or HIF-2 α and further decreased when both HIF-α s were absent. Conversely, basal phosphorylation of H2AX was increased in cells with constitutively stabilized HIF-2 α . These results suggest that both HIF-1 and HIF-2 are involved in γ H2AX accumulation by tumor hypoxia, which might increase a cancer cell ' s capacity to repair DNA damage, contributing to tumor therapy resistance.

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Section: Hypoxic γ H2ax Accumulation Is Hif Dependentsupporting

confidence: 73%

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia

Wrann

Kaufmann²,

Wirthner³

et al. 2013

Biological Chemistry

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“…Previous work with non-RCC cells has indicated that although the large majority of hypoxia inducible genes are responsive to HIF-1a (Hu et al, 2003;Park et al, 2003;Sowter et al, 2003;Manalo et al, 2005;Wang et al, 2005), two distinct patterns of response are observed with some genes being exclusively responsive to HIF-1a and some responding to both HIF-1a and HIF-2a. In RCC cells, this transcriptional selectivity is more marked with the former group of genes remaining exclusively responsive to HIF-1a and the latter becoming dominantly, or even exclusively, responsive to HIF-2a (Sowter et al, 2003;Raval et al, 2005).…”

Section: Resultsmentioning

confidence: 98%

Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms

Lau¹,

Tian²,

Raval³

et al. 2007

Br J Cancer

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Inactivation of the von Hippel -Lindau tumour suppressor in renal cell carcinoma (RCC) leads to failure of proteolytic regulation of the a subunits of hypoxia-inducible factor (HIF), constitutive upregulation of the HIF complex, and overexpression of HIF target genes. However, recent studies have indicated that in this setting, upregulation of the closely related HIF-a isoforms, HIF-1a and HIF-2a, have contrasting effects on tumour growth, and activate distinct sets of target genes. To pursue these findings, we sought to elucidate the mechanisms underlying target gene selectivity for HIF-1a and HIF-2a. Using chromatin immunoprecipitation to probe binding to hypoxia response elements in vivo, and expression of chimaeric molecules bearing reciprocal domain exchanges between HIF-1a and HIF-2a molecules, we show that selective activation of HIF-a target gene expression is not dependent on selective DNAbinding at the target locus, but depends on non-equivalent C-terminal portions of these molecules. Our data indicate that post-DNA binding mechanisms that are dissimilar for HIF-1a and HIF-2a determine target gene selectivity in RCC cells.

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“…Although structurally highly similar, specific roles of HIF-a isoforms in tumorigenesis have been defined Semenza, 2010). Pioneering work using genetically modified mouse embryonic fibroblast with targeted disruption of both Hif1a alleles suggested a predominant role of HIF-1a for regulating gene expression in response to hypoxia (Park et al, 2003), a finding that was confirmed for a limited number of classical HIF target genes in human cell lines by using transient RNA interference against both HIF-a isoforms (Sowter et al, 2003). However, expression analyses in a renal clear cell carcinoma-derived cell line deficient for HIF-1a revealed preserved hypoxic induction of many known HIF target genes, indicating that effectively both HIF-a isoforms contribute to hypoxia-induced transcription (Hu et al, 2003).…”

Section: Introductionmentioning

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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Hypoxia-Induced Gene Expression Occurs Solely through the Action of Hypoxia-Inducible Factor 1α (HIF-1α): Role of Cytoplasmic Trapping of HIF-2α

Cited by 163 publications

References 47 publications

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia

Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms

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

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