A5067748893- DNA and Nucleic Acid Chemistry
- RNA Interference and Gene Delivery
- Advanced biosensing and bioanalysis techniques
- Axon Guidance and Neuronal Signaling
- RNA and protein synthesis mechanisms
- Pain Mechanisms and Treatments
- Inflammatory mediators and NSAID effects
- Estrogen and related hormone effects
- Telomeres, Telomerase, and Senescence
- Microtubule and mitosis dynamics
- Alzheimer's disease research and treatments
- Lung Cancer Treatments and Mutations
- Protein Degradation and Inhibitors
- Synthesis and biological activity
- Neurogenetic and Muscular Disorders Research
- Amyotrophic Lateral Sclerosis Research
- Computational Drug Discovery Methods
- RNA Research and Splicing
- Cancer Research and Treatments
- Click Chemistry and Applications
- PI3K/AKT/mTOR signaling in cancer
- RNA regulation and disease
- Protein Kinase Regulation and GTPase Signaling
- Down syndrome and intellectual disability research
- Neuroscience and Neuropharmacology Research
University of Arizona
2015-2025
SilaGene (United States)
2019-2024
BIO5 Institute
2016-2021
University of Arizona Cancer Center
2012-2020
Institute of Pharmacology
2009-2014
The University of Tokyo
2005
Arizona Oncology
2004
The nuclease hypersensitivity element III1 (NHE III1) upstream of the P1 and P2 promoters c-MYC controls 80-90% transcriptional activity this gene. purine-rich strand in region can form a G-quadruplex structure that is critical part silencer for promoter. We have demonstrated mixture four biologically relevant parallel-loop isomers, which upon interaction with cationic porphyrin TMPyP4 are converted to mixed parallel/antiparallel structures.
It is generally accepted that DNA predominantly exists in duplex form cells. However, under torsional stress imposed by active transcription, can assume nonduplex structures. The BCL2 promoter region forms two different secondary structures on opposite strands called the G-quadruplex and i-motif. i-motif a highly dynamic structure equilibrium with flexible hairpin species. Here we identify pregnanol derivative class of piperidine derivatives differentially modulate gene expression...
Cationic porphyrins are known to bind and stabilize different types of G-quadruplexes. Recent studies have shown the biological relevance intramolecular parallel G-quadruplex as a transcriptional silencer in c-MYC promoter. TMPyP4 also binds this most likely converts it mixed parallel/antiparallel with two external lateral loops one internal propeller loop, suppressing activation. To achieve therapeutic selectivity by targeting G-quadruplexes, is necessary synthesize drugs that can...
A polypurine (guanine)/polypyrimidine (cytosine)-rich sequence within the proximal promoter region of human RET oncogene has been shown to be essential for basal transcription. Specifically, G-rich strand this consists five consecutive runs guanines, which is consistent with general motif capable forming intramolecular G-quadruplexes. Here we demonstrate that, in presence 100 mM K+, ability adopt two G-quadruplex structures vitro. Moreover, comparative circular dichroism (CD) and DMS...
The proximal 5'-flanking region of the human platelet-derived growth factor A (PDGF-A) promoter contains one nuclease hypersensitive element (NHE) that is critical for PDGF-A gene transcription. On basis circular dichroism (CD) and electrophoretic mobility shift assay (EMSA), we have shown guanine-rich (G-rich) strand DNA in this can form stable intramolecular parallel G-quadruplexes under physiological conditions. Taq polymerase stop has G-rich NHE two major G-quadruplex structures, which...
Abstract Previous studies on the functional analysis of human vascular endothelial growth factor (VEGF) promoter using full-length VEGF reporter revealed that proximal 36-bp region (−85 to −50 relative transcription initiation site) is essential for basal or inducible activity in several cancer cells. This consists a polypurine (guanine) tract contains four runs at least three contiguous guanines separated by one more bases, thus conforming general motif capable forming an intramolecular...
A polyguanine/polycytosine (polyG/polyC) tract in the proximal promoter of vascular endothelial growth factor (VEGF) gene is essential for transcriptional activation. The guanine-rich (G-rich) and cytosine-rich (C-rich) strands on this are shown to form specific secondary structures, characterized as G-quadruplexes i-motifs, respectively. Mutational analysis G-rich strand combined with dimethyl sulfate (DMS) footprinting, a polymerase stop assay, circular dichroism (CD) spectroscopy revealed...
Most transcription of the MYC proto-oncogene initiates in near upstream promoter, within which lies nuclease hypersensitive element (NHE) III(1) region containing CT-element. This dynamic stretch DNA can form at least three different topologies: single-stranded DNA, double-stranded or higher order secondary structures that silence transcription. In current report, we identify ellipticine analog GQC-05 (NSC338258) as a high affinity, potent, and selective stabilizer G-quadruplex (G4). cells,...
This G-rich region of the c-MYC promoter has been shown to form a G-quadruplex structure that acts as silencer element for transcriptional control. In present work, we have synthesized series 11-substituted quindoline analogues G-quadruplex–stabilizing compounds, and cell-free in vitro activity these compounds were evaluated. Two lead (4 12) demonstrated good profiles, compound 4 (2-(4-(10H-indolo[3,2-b]quinolin-11-yl)piperazin-1-yl)-N,N-dimethylethanamine) significantly down-regulated...
There is an urgent need for the development of new therapeutic strategies Alzheimer's disease (AD). The dual-specificity tyrosine phosphorylation-regulated kinase-1A (Dyrk1a) a protein kinase that phosphorylates amyloid precursor (APP) and tau thus represents link between two key proteins involved in AD pathogenesis. Furthermore, Dyrk1a upregulated postmortem human brains, high levels are associated with mental retardation. Here, we sought to determine effects Dyrk1 inhibition on AD-like...
Activation of human telomerase reverse transcriptase (hTERT) is necessary for limitless replication in tumorigenesis. Whereas hTERT transcriptionally silenced normal cells, most tumor cells reactivate expression by alleviating transcriptional repression through diverse genetic and epigenetic mechanisms. Transcription-activating promoter mutations have been found to occur at high frequencies multiple cancer types. These shown form new transcription factor binding sites that drive expression,...
Abstract The formation of G-quadruplex structures within the nuclease hypersensitive element (NHE) III1 region c-myc promoter and ability these to repress transcription have been well established. However, just how extremely stable DNA secondary are transformed activate is still unknown. NM23-H2/nucleoside diphosphate kinase B has recognized as an activator via interactions with NHE gene promoter. Through use RNA interference, we confirmed transcriptional regulatory role NM23-H2. In...
The platelet-derived growth factor receptor β (PDGFR-β) signaling pathway is a validated and important target for the treatment of certain malignant nonmalignant pathologies. We previously identified G-quadruplex-forming nuclease hypersensitive element (NHE) in human PDGFR-β promoter that putatively forms four overlapping G-quadruplexes. Therefore, we further investigated structures biological roles G-quadruplexes i-motifs NHE with ultimate goal demonstrating an alternate effective strategy...
The discovery of G-quadruplexes and other DNA secondary elements has increased the structural diversity well beyond ubiquitous double helix. However, it remains to be determined whether tertiary interactions can take place in a complex that contains more than one structure. Using new data analysis strategy exploits hysteresis region between mechanical unfolding refolding traces obtained by laser-tweezers instrument, we now provide first convincing kinetic thermodynamic evidence higher order...
Sequences with the potential to form RNA G-quadruplexes (G4s) are common in mammalian introns, especially proximity of 5′ splice site (5′SS). However, difficulty demonstrating that G4s pre-mRNA functional conditions has meant little is known about their effects or mechanisms action. We have shown previously two Bcl-X pre-mRNA, one close each alternative 5′SS. If these affect splicing but competition other structures binding proteins, then ligands stabilize them would increase proportion...
RNA dysregulation likely contributes to disease pathogenesis of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. A pathological form the transactive response (TAR) DNA binding protein (TDP-43) binds in stress granules forms membraneless, amyloid-like TDP-43 aggregates cytoplasm ALS motor neurons. In this study, we hypothesized that by targeting recognition motif (RRM) domains confer a pathogenic interaction between RNA, neuron toxicity could be reduced. silico...
Protein-protein interaction inhibitor of the sodium NaV1.7 channel has analgesic effects in preclinical models pain.
We previously reported that destruction of the small ubiquitin-like modifier (SUMO) modification site in axonal collapsin response mediator protein 2 (CRMP2) was sufficient to selectively decrease trafficking voltage-gated sodium channel NaV1.7 and reverse neuropathic pain. Here, we further interrogate biophysical nature interaction between CRMP2 SUMOylation machinery, test hypothesis a rationally designed motif (CSM) peptide can interrupt E2 SUMO-conjugating enzyme Ubc9-dependent leading...
Abstract AKT, a phospholipid-binding serine/threonine kinase, is key component of the phosphoinositide 3-kinase cell survival signaling pathway that aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains be achieved. We developed novel strategy AKT by targeting pleckstrin homology (PH) domain. Using silico library screening and interactive molecular docking, we identified class non–lipid-based compounds bind selectively PH domain...
N-type voltage-gated calcium (Cav 2.2) channels are critical determinants of increased neuronal excitability and neurotransmission accompanying persistent neuropathic pain. Although Cav 2.2 channel antagonists recommended as first-line treatment for pain, calcium-current blocking gabapentinoids inadequately alleviate chronic pain symptoms often exhibit numerous side effects. Collapsin response mediator protein 2 (CRMP2) targets to the sensory neuron membrane allosterically modulates their...