Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist

Olenyuk, Bogdan; Zhang, Guojun; Klco, Jeffery M.; Nickols, Nicholas G.; Kaelin, William G.; Dervan, Peter B.

doi:10.1073/pnas.0407617101

Cited by 205 publications

(184 citation statements)

References 43 publications

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“…35,36 Aminolysis furnishes the polyamide, which can be further derivatized on the turn or tail residues. The selection of either β-Ala-PAM or Kaiser oxime resin yields different C-terminal groups following cleavage with a primary 6).…”

Section: Hairpin Polyamide Motifmentioning

confidence: 99%

“…35 Each of the nine polyamides was assayed on a plasmid containing its 7-bp match site according to the pairing rules, as well as three formal mismatch binding sites (Table 2. at a given DNA binding site. Comparing these constants across the four potential binding sites allows a relative measure of specifi city for each base pair at the targeted position.…”

Section: Dna Binding Energetics Quantitative Dnase I Footprint Titramentioning

confidence: 99%

“…39 PCR products (295 bp, 5'-32 P-end-labeled) were isolated and DNase I footprint titrations were performed according to standard protocols. 35 Chemical sequencing reactions were performed according to published methods. 40,41 2000, 97, 3930-3935.…”

Section: Dnase I Footprinting Experimentsmentioning

confidence: 99%

“…Notably, Utf1 mRNA was decreased to a level comparable to that of the RNAi control, and the Sox2 mRNA level increased two-fold. 28,33,35 The time course for the 48-hour incubation experiment is illustrated in Figure 5.12. At t = 0 h, R1 cells were plated in a 24-well format.…”

Section: ' -G C a C C T T T G T T A T G C A T C T G C C G -3 ' 3 ' -Cmentioning

confidence: 99%

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Completion of a programmable DNA-binding small molecule library

et al. 2007

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Section: Hairpin Polyamide Motifmentioning

confidence: 99%

Section: Dna Binding Energetics Quantitative Dnase I Footprint Titramentioning

confidence: 99%

Section: Dnase I Footprinting Experimentsmentioning

confidence: 99%

Section: ' -G C a C C T T T G T T A T G C A T C T G C C G -3 ' 3 ' -Cmentioning

confidence: 99%

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Completion of a programmable DNA-binding small molecule library

et al. 2007

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“…1) (15,16). This class of molecules has been shown to regulate target genes in human cells and in mouse models of disease (13,17,18). Hairpin polyamides are typically composed of pyrrole and imidazole rings and can be engineered, using simple recognition rules (16), to target specific 6-12 base pair (bp) sequences (Fig.…”

mentioning

confidence: 99%

Specificity landscapes of DNA binding molecules elucidate biological function

Carlson

Warren

Hauschild

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

151

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Evaluating the specificity spectra of DNA binding molecules is a nontrivial challenge that hinders the ability to decipher gene regulatory networks or engineer molecules that act on genomes.Here we compare the DNA sequence specificities for different classes of proteins and engineered DNA binding molecules across the entire sequence space. These high-content data are visualized and interpreted using an interactive "specificity landscape" which simultaneously displays the affinity and specificity of a million-plus DNA sequences. Contrary to expectation, specificity landscapes reveal that synthetic DNA ligands match, and often surpass, the specificities of eukaryotic DNA binding proteins. The landscapes also identify differential specificity constraints imposed by diverse structural folds of natural and synthetic DNA binders. Importantly, the sequence context of a binding site significantly influences binding energetics, and utilizing the full contextual information permits greater accuracy in annotating regulatory elements within a given genome. Assigning such context-dependent binding values to every DNA sequence across the genome yields predictive genome-wide binding landscapes (genomescapes). A genomescape of a synthetic DNA binding molecule provided insight into its differential regulatory activity in cultured cells. The approach we describe will accelerate the creation of precision-tailored DNA therapeutics and uncover principles that govern sequence-specificity of DNA binding molecules.

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Hypoxic Response and Associated Diseases

Emily¹,

Loenarz²,

Schofield³

2008

Wiley Encyclopedia of Chemical Biology

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Animals must respond efficiently to changes in oxygen levels. This response is achieved via oxygen‐dependent regulation of a heterodimeric hypoxia‐inducible transcription factor (HIF), which enables upregulation of genes that assist in the hypoxic response. Posttranslational hydroxylation of the HIF‐α subunit at either of two conserved prolyl residues enables binding to the von Hippel–Lindau protein elongin C/B complex that targets HIF‐α for degradation via the ubiquitin proteasome pathway. Hydroxylation of an asparaginyl residue in the C‐terminal transcriptional activation domain of HIF‐α blocks its interaction with the transcriptional coactivator p300. The HIF prolyl and asparaginyl hydroxylases are oxygen dependent; therefore, their regulation of HIF directly links changes in oxygen concentration and the physiological response to hypoxia. The hypoxic response is implicated in a range of disease states, including cancer, ischemia, and heart disease. Manipulation of the HIF system for therapeutic advantage is therefore an area of medicinal interest.

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Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist

Cited by 205 publications

References 43 publications

Completion of a programmable DNA-binding small molecule library

Completion of a programmable DNA-binding small molecule library

Specificity landscapes of DNA binding molecules elucidate biological function

Hypoxic Response and Associated Diseases

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