Identification by phage display of single-domain antibody fragments specific for the ODD domain in hypoxia-inducible factor 1alpha

Groot, Arjan J.; Verheesen, Peter; Westerlaken, Elike J; Gort, Eelke H.; Groep, Petra van der; Bovenschen, Niels; Wall, Elsken van der; Diest, Paul J. van; Шварц, Анна

doi:10.1038/labinvest.3700395

Cited by 33 publications

(20 citation statements)

References 40 publications

(49 reference statements)

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“…Recombinant HIF-1α protein was prepared using immobilized metal ion affinity chromatography (IMAC), using a fused His6 tag as previously described (45). Recombinant COMMD1-GST fulllength (used in Supplemental Figure 6) was prepared as previously described (46).…”

Section: Methodsmentioning

confidence: 99%

COMMD1 disrupts HIF-1α/β dimerization and inhibits human tumor cell invasion

Sluis¹,

Mao²,

Zhai³

et al. 2010

J. Clin. Invest.

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109

136

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The gene encoding COMM domain-containing 1 (COMMD1) is a prototypical member of the COMMD gene family that has been shown to inhibit both NF-κB-and HIF-mediated gene expression. NF-κB and HIF are transcription factors that have been shown to play a role in promoting tumor growth, survival, and invasion. In this study, we demonstrate that COMMD1 expression is frequently suppressed in human cancer and that decreased COMMD1 expression correlates with a more invasive tumor phenotype. We found that direct repression of COMMD1 in human cell lines led to increased tumor invasion in a chick xenograft model, while increased COMMD1 expression in mouse melanoma cells led to decreased lung metastasis in a mouse model. Decreased COMMD1 expression also correlated with increased expression of genes known to promote cancer cell invasiveness, including direct targets of HIF. Mechanistically, our studies show that COMMD1 inhibits HIF-mediated gene expression by binding directly to the amino terminus of HIF-1α, preventing its dimerization with HIF-1β and subsequent DNA binding and transcriptional activation. Altogether, our findings demonstrate a role for COMMD1 in tumor invasion and provide a detailed mechanism of how this factor regulates the HIF pathway in cancer cells.

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Section: Methodsmentioning

confidence: 99%

COMMD1 disrupts HIF-1α/β dimerization and inhibits human tumor cell invasion

Sluis¹,

Mao²,

Zhai³

et al. 2010

J. Clin. Invest.

Self Cite

109

136

View full text Add to dashboard Cite

show abstract

“…This Ainp1 phage display peptide may serve as a prototype of a new line of anticancer agents since many phage display-derived peptides have been extensively developed as alternatives to antibodies for therapeutic purpose [24]. In particular, a few peptides which interact with either HIF-1 or HIF-1 downstream targets have been developed using the phage display method for diagnostic or therapeutic purpose [14, 25]. …”

Section: Discussionmentioning

confidence: 99%

A cell-penetrating peptide suppresses the hypoxia inducible factor-1 function by binding to the helix-loop-helix domain of the aryl hydrocarbon receptor nuclear translocator

Wang

Thompson

Chan

2013

Chemico-Biological Interactions

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The heterodimeric hypoxia inducible factor-1 (HIF-1) complex is composed of the hypoxia inducible factor-1 alpha (HIF-1α) and the aryl hydrocarbon receptor nuclear translocator (ARNT). Activation of the HIF-1 function is essential for tumor growth and metastasis. We previously showed that transfection of a plasmid containing an ARNT-interacting peptide (Ainp1) cDNA suppresses the HIF-1 signaling in Hep3B cells. Here we generated TAT fusion of the Ainp1 peptide (6His-TAT-Ainp1) to determine whether and how the Ainp1 peptide suppresses the HIF-1 function. The bacterially expressed 6His-TAT-Ainp1 was purified under denatured condition and then refolded by limited dialysis. The refolded 6His-TAT-Ainp1 interacts with the helix-loop-helix (HLH) domain of ARNT in a similar fashion as the native 6His-Ainp1. 6His-TAT-Ainp1 colocalizes with ARNT in the nucleus of HeLa and Hep3B cells after protein transduction. The transduced protein reaches the maximum intracellular levels within 2 h while remains detectable up to 96 h in HeLa cells. At 2 µM concentration, 6His-TAT-Ainp1 is not cytotoxic in HeLa cells but suppresses the cobalt chloride-activated, hypoxia responsive enhancer-driven luciferase expression in a dose-dependent manner. In addition, it decreases the cobalt chloride-dependent induction of the HIF-1 target genes at both the message (vascular endothelial growth factor and aldolase C) and protein (carbonic anhydrase IX and glucose transporter 1) levels. The protein levels of HIF-1α and ARNT are not altered in the presence of 6His-TAT-Ainp1. In summary, we provided evidence to support that the Ainp1 peptide directly suppresses the HIF-1 function by interacting with the ARNT HLH domain, and in turn interfering with the heterodimerization of HIF-1α and ARNT.

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“…This could then protect transplanted and possible host cells from the hypoxia. 7,8,28,29 Several elements, such as the hypoxia-responsive untranslated region, [30][31][32] oxygen-dependant degradation domain sequence, 33,34 RTP801 promoter 35 and Epo enhancer 31,36 have been used to design hypoxia-inducible systems. We have previously confirmed that the Epo enhancer-based system increases gene expression specifically in hypoxic cells.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-specific GM-CSF-overexpressing neural stem cells improve graft survival and functional recovery in spinal cord injury

Kim

et al. 2011

Gene Ther

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine that stimulates the differentiation and function of hematopoietic cells. GM-CSF has been implicated in nervous system function. The goal of the present study was to understand the effects of hypoxia-induced GM-CSF on neural stem cells (NSCs) in a model of spinal cord injury (SCI). GM-CSF-overexpressing NSCs were engineered utilizing a hypoxia-inducible gene expression plasmid, including an Epo enhancer ahead of an SV promoter (EpoSV-GM-CSF). Cells were then subjected to hypoxia (pO 2 , 1%) or a hypoxia-mimicking reagent (CoCl 2 ) in vitro. The progression of time of GM-CSF expression was tracked in EpoSV-GM-CSF-transfected NSCs. Overexpression of GM-CSF in undifferentiated and differentiated NSCs created resistance to H 2 O 2 -induced apoptosis in hypoxia. NSCs transfected with EpoSV-GM-CSF or SV-GM-CSF were transplanted into rats after SCI to assess the effect of GM-CSF on NSC survival and restoration of function. Moreover, a significantly higher amount of surviving NSCs and neuronal differentiation was observed in the EpoSV-GM-CSF-treated group. Significant improvement in locomotor function was also found in this group. Thus, GM-CSF overexpression by the Epo enhancer in hypoxia was beneficial to transplanted NSC survival and to behavioral improvement, pointing toward a possible role for GM-CSF in the treatment of SCI.

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Identification by phage display of single-domain antibody fragments specific for the ODD domain in hypoxia-inducible factor 1alpha

Cited by 33 publications

References 40 publications

COMMD1 disrupts HIF-1α/β dimerization and inhibits human tumor cell invasion

COMMD1 disrupts HIF-1α/β dimerization and inhibits human tumor cell invasion

A cell-penetrating peptide suppresses the hypoxia inducible factor-1 function by binding to the helix-loop-helix domain of the aryl hydrocarbon receptor nuclear translocator

Hypoxia-specific GM-CSF-overexpressing neural stem cells improve graft survival and functional recovery in spinal cord injury

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