Feedback regulators of hypoxia-inducible factors and their role in cancer biology

Henze, Anne-Theres; Acker, Till

doi:10.4161/cc.9.14.12249

Cited by 56 publications

(44 citation statements)

References 193 publications

(270 reference statements)

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“…A complex of regulatory mechanisms involved in the hypoxic response via modulation of the stability and transcriptional activity of HIF-1a has been reported (42)(43)(44)(45)(46)(47)(48). Notably, regulators of HIF-1a also contribute to hypoxia-mediated biologic processes through fine-tuning of HIF-1a expression and activity.…”

Section: Discussionmentioning

confidence: 99%

A Negative Feedback of the HIF-1α Pathway via Interferon-Stimulated Gene 15 and ISGylation

Yeh

Yang

Hsieh

et al. 2013

Clinical Cancer Research

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Purpose: The IFN-stimulated gene 15 (ISG15)-and ubiquitin-conjugation pathways play roles in mediating hypoxic and inflammatory responses. To identify interaction(s) between these two tumor microenvironments, we investigated the effect of ISG15 on the activity of the master hypoxic transcription factor HIF-1a.Experimental Design: IFN and desferoxamine treatments were used to induce the expression of ISGs and HIF-1a, respectively. Interactions between HIF-1a and the ISG15 and ISGylation system were studied using knockdown of mRNA expression, immunoblotting, coimmunoprecipitation, and pull-down analyses. Effects of the ISG15 and ISGylation system on the HIF-1a-directed processes were examined using reporter, reverse transcription polymerase chain reaction (RT-PCR), and tumorigenic growth assays.Results: We found that the level of the free form of HIF-1a is differentially regulated by IFN treatment, and that the free ISG15 level is lower under hypoxia. Mechanism-directed studies have shown that HIF-1a not only interacts physically with ISG15, but is also ISGylated in multiple domains. ISG15 expression disrupts the functional dimerization of HIF-1a and -1b. Subsequently, expression of the ISG15 and/or ISGylation system attenuates HIF-1a-mediated gene expression and tumorigenic growth.Conclusion: In summary, our results revealed cross-talk between inflammatory and hypoxic pathways through the ISGylation of HIF-1a. On the basis of these results, we propose a novel negative feedback loop for the HIF-1a-mediated pathway involving the regulation of HIF-1a via IFN-induced ISGylation.

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Section: Discussionmentioning

confidence: 99%

A Negative Feedback of the HIF-1α Pathway via Interferon-Stimulated Gene 15 and ISGylation

Yeh

Yang

Hsieh

et al. 2013

Clinical Cancer Research

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“…Other factors independent of hypoxia can also promote HIF-1A protein accumulation via translational or post-translational mechanisms (28). Several studies have shown that many human cancers express an elevated level of HIF-1A protein, which is closely associated with a more aggressive tumor phenotype (29)(30)(31)(32) and offers resistance to radiotherapy and anticancer chemotherapy (33,34).…”

Section: Normal Tissue Cancerous Tissue -----------------------------mentioning

confidence: 99%

Increased expression of HIF-1A and its implication in the hypoxia pathway in primary advanced uterine cervical carcinoma

Łuczak

Roszak²,

Pawlik³

et al. 2011

Oncol Rep

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Abstract. The development of cervical cancer exhibits some unique differences compared to other solid tumors. Normal cervical stratified epithelia have characteristics of hypoxic tissue. Lack of oxygen (hypoxia) induces the HIF-1 (hypoxiainducible factor-1) transcription factor, which is a heterodimer composed of a constitutively expressed β subunit and a hypoxia-inducible α-subunit. HIF-1A targets the transcription of over 70 genes involved in many aspects of cancer biology. In well-oxygenated environments, the HIF-1A subunit is hydroxylated, recognized and marked for proteosomal destruction by an E3 ubiquitin ligase, the von Hippel-Lindau protein (pVHL) complex. Under hypoxic stress, proline hydroxylase (PHD) activity is diminished, and stabilized HIF-1A is involved in the activation of the tissue response to hypoxia. Here, we examined the HIF-1A and VHL transcript levels and HIF-1A protein levels in cancerous tissue (n=30) and non-cancerous, normal uterine cervical tissue (n=30). We also compared the methylation status of HIF-1A and of the VHL promoter regions in cancerous and normal tissue samples. Significantly higher levels of HIF-1A and VHL transcripts (p<0.0001 and p= 0.0042, respectively) and of HIF-1A protein (p= 0.0037) were detected in cancerous tissue compared to normal samples. We did not observe DNA methylation in the HIF-1A and VHL promoter region in either control or cancerous tissue samples. VHL has a functional hypoxia response element (HRE) in the promoter region, and the induction of this HRE acts within a negative feedback loop to limit the hypoxic HIF-1A response. Our findings may suggest that HIF-1A could promote its own degradation by the induction of VHL gene expression (Spearman correlation coefficient, 0.515; p=0.003). Our study shows for the first time that this increase in VHL expression could be HIF-1A-dependent and serves within a negative feedback pathway during hypoxia to regulate the cell-specific oxygen threshold for HIF-1A activation.

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“…1), thus completing the feedback loop. [13][14][15][16][17][18][19][20][21][22][23][24][25][26] PHDs (preferentially PHD2 17,21 ) control HIF-1α under normal conditions, keeping its levels low ( Fig. 2A).…”

Section: -12mentioning

confidence: 99%

The purpose of the HIF-1/PHD feedback loop: To limit mTOR-induced HIF-1α

Demidenko¹,

Blagosklonny²

2011

Cell Cycle

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Feedback regulators of hypoxia-inducible factors and their role in cancer biology

Cited by 56 publications

References 193 publications

A Negative Feedback of the HIF-1α Pathway via Interferon-Stimulated Gene 15 and ISGylation

A Negative Feedback of the HIF-1α Pathway via Interferon-Stimulated Gene 15 and ISGylation

Increased expression of HIF-1A and its implication in the hypoxia pathway in primary advanced uterine cervical carcinoma

The purpose of the HIF-1/PHD feedback loop: To limit mTOR-induced HIF-1α

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