Nadya Tarasova

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Papers by Nadya Tarasova

Development of a Novel Peptide Nanoparticle Inhibitor for Human CCR3/Eotaxin-Mediated Eosinophil Migration

by Nadya Tarasova, Vadim Gaponenko, and Steven Ackerman

Journal of Allergy and Clinical Immunology, 2015

GTP-Dependent K-Ras Dimerization

by Nadya Tarasova and Vadim Gaponenko

Structure, 2015

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Heteromerization of chemokine (C-X-C motif) receptor 4 with α1A/B-adrenergic receptors controls α1-adrenergic receptor function

by Nadya Tarasova, Kenneth Byron, and Vadim Gaponenko

Proceedings of the National Academy of Sciences of the United States of America, Jan 31, 2015

Recent evidence suggests that chemokine (C-X-C motif) receptor 4 (CXCR4) contributes to the regul... more Recent evidence suggests that chemokine (C-X-C motif) receptor 4 (CXCR4) contributes to the regulation of blood pressure through interactions with α1-adrenergic receptors (ARs) in vascular smooth muscle. The underlying molecular mechanisms, however, are unknown. Using proximity ligation assays to visualize single-molecule interactions, we detected that α1A/B-ARs associate with CXCR4 on the cell surface of rat and human vascular smooth muscle cells (VSMC). Furthermore, α1A/B-AR could be coimmunoprecipitated with CXCR4 in a HeLa expression system and in human VSMC. A peptide derived from the second transmembrane helix of CXCR4 induced chemical shift changes in the NMR spectrum of CXCR4 in membranes, disturbed the association between α1A/B-AR and CXCR4, and inhibited Ca(2+) mobilization, myosin light chain (MLC) 2 phosphorylation, and contraction of VSMC upon α1-AR activation. CXCR4 silencing reduced α1A/B-AR:CXCR4 heteromeric complexes in VSMC and abolished phenylephrine-induced Ca(2+...

Small molecule inhibitor of HIV-1 cell fusion blocks chemokine receptor-mediated function

by O. Howard and Nadya Tarasova

Journal of leukocyte biology, 1998

The intersection of the HIV and the chemokine fields began with the observation that HIV entry in... more The intersection of the HIV and the chemokine fields began with the observation that HIV entry into cells could be blocked by certain chemokines. Subsequent work showed that HIV entry is dependent on the presence of specific chemokine receptors. These observations led us to evaluate a series of compounds, ureido analogs of distamycin previously reported to block HIV entry into cells in vitro, for chemokine antagonist activity. One of the distamycin analogs, 2,2'[4,4'-[[aminocarbonyl]amino]bis[N,4'-di[pyrrole-2-carboxamide- 1,1'-dimethyl]]-6,8 napthalenedisulfonic acid] hexasodium salt (NSC 651016), is shown here to inhibit syncytia formation and cell fusion. Mechanistic studies showed that this inhibition was not due to conformational changes in gp120-gp41 induced by target cell CD4 and chemokine co-receptor and was therefore not due to interference with binding of HIV-1. Additional mechanistic studies demonstrated that NSC 651016 inhibited chemokine binding to speci...

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A new role for STAT3 as a regulator of chromatin topology

by Nadya Tarasova, Sergey Chasovskikh, and Anatoly Dritschilo

Transcription, 2013

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STAT1 activation regulates proliferation and differentiation of renal progenitors

Cellular Signalling, 2010

We have shown previously that activation of STAT1 contributes to the pathogenesis of Wilms tumor.... more We have shown previously that activation of STAT1 contributes to the pathogenesis of Wilms tumor. This neoplasm caricatures metanephric development and is believed to originate from embryonic renal mesenchymal progenitors that lose their ability to undergo mesenchymal–epithelial transition (MET). Therefore, we hypothesized that STAT1 is also activated and functional during metanephric development. Here we have demonstrated that both STAT1 and

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Protein/Peptide Transduction in Metanephric Explant Culture

Methods in Molecular Biology, 2013

While gene targeting methods have largely supplanted cell/explant culture models for studying dev... more While gene targeting methods have largely supplanted cell/explant culture models for studying developmental processes, they have not eliminated the need for or value of such approaches in the investigator&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s technical arsenal. Explant culture models, such as those devised for the metanephric kidney and its progenitors, remain invaluable as tools for screening regulatory factors involved in tissue induction or in the inhibition of progenitor specification. Thus, some factors capable of inducing tissue condensations or nephronic tubule formation in explants of metanephric mesenchyme have been identified through direct treatment of cultures rather than lengthy genetic engineering in animals. Unfortunately, renal progenitors are largely refractory to most contemporary methods for gene manipulation, including transfection and viral transduction, so the applications of explant culture have been rather limited. However, methods for protein or peptide transduction offer greatly improved efficiencies for uptake and expression/regulation of proteins within cells and tissues. Biologically active TAT- or penetratin-fusion proteins/peptides are readily taken up by most cells in metanephric explants or monolayer cultured cells (Plisov et al., J Am Soc Nephrol 16:1632-1644, 2005; Osafune et al., Development 133:151-161, 2006; Wang et al., Cell Signal 22:1717-1726, 2010; Tanigawa, Dev Biol 352:58-69, 2011), allowing a direct functional evaluation of theoretically any protein, including biologically active enzymes and transcription factors, or any targeted interactive domain within a protein.

Gastrin receptor expression and function during rapid transformation of the enterochromaffin-like cells in an African rodent

Regulatory Peptides, 1997

The enterochromaffin-like cell (ECL) cells of the stomach are principally regulated by gastrin vi... more

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Crystal structure of human pepsin and its complex with pepstatin

Protein Science, 2008

The three-dimensional crystal structure of human pepsin and that of its complex with pepstatin ha... more The three-dimensional crystal structure of human pepsin and that of its complex with pepstatin have been solved by X-ray crystallographic methods. The native pepsin structure has been refined with data collected to 2.2 A resolution to an R-factor of 19.7%. The pepsin:pepstatin structure has been refined with data to 2.0 A resolution to an R-factor of 18.5%. The hydrogen bonding interactions and the conformation adopted by pepstatin are very similar to those found in complexes of pepstatin with other aspartic proteinases. The enzyme undergoes a conformational change upon inhibitor binding to enclose the inhibitor more tightly. The analysis of the binding sites indicates that they form an extended tube without distinct binding pockets. By comparing the residues on the binding surface with those of the other human aspartic proteinases, it has been possible to rationalize some of the experimental data concerning the different specificities. At the S1 site, valine at position 120 in renin instead of isoleucine, as in the other enzymes, allows for binding of larger hydrophobic residues. The possibility of multiple conformations for the P2 residue makes the analysis of the S2 site difficult. However, it is possible to see that the specific interactions that renin makes with histidine at P2 would not be possible in the case of the other enzymes. At the S3 site, the smaller volume that is accessible in pepsin compared to the other enzymes is consistent with its preference for smaller residues at the P3 position.

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Crystal and Molecular Structures of Human Progastricsin at 1.62 Å Resolution

Journal of Molecular Biology, 1995

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Transmembrane Inhibitors of P-Glycoprotein, an ABC Transporter

Journal of Medicinal Chemistry, 2005

Drug resistance mediated by ABC transporters such as P-glycoprotein (P-gp) continues to be a majo... more Drug resistance mediated by ABC transporters such as P-glycoprotein (P-gp) continues to be a major impediment to effective cancer chemotherapy. We have developed a panel of highly specific peptide inhibitors of P-gp based on the structure of the transmembrane domains of the transporter. These peptides are thought to exert their inhibitory action by disrupting the proper assembly of P-gp. A novel 96-well-plate assay based on the efflux of fluorescent P-gp substrate DiOC 2 (3-ethyl-2-[3-(3-ethyl-2(3H)-benzoxazolylidene)-1-propenyl]benzoxazolium iodide) was developed and used for structure-functional characterization of transporter inhibitors. The studies strongly suggest that potent and selective inhibitors of ABC transporters can now be developed solely on the basis of the primary structures of the target proteins. The inhibition of P-gp with transmembrane peptides was shown to be chirality-independent. A 25-residue long retroinverso D-analogue of transmembrane domain 5 inhibited the efflux of the fluorescent P-gp substrate with an IC 50 of 500 nM. Transmembrane peptides effectively sensitized resistant cancer cells to doxorubicin in vitro without demonstrating any cell toxicity of their own. The newly synthesized P-gp antagonists appear to be promising nontoxic drug resistance inhibitors that merit further development.

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Structural Analogues of Smoothened Intracellular Loops as Potent Inhibitors of Hedgehog Pathway and Cancer Cell Growth

Journal of Medicinal Chemistry, 2007

Smoothened is a critical component of the Hedgehog pathway that is essential for stem cell renewa... more Smoothened is a critical component of the Hedgehog pathway that is essential for stem cell renewal and is dysregulated in many cancer types. We have found synthetic analogues of the second and third intracellular loops of smoothened to be potent inhibitors of the Hedgehog pathway. Palmitoylated peptides as short as 10 residues inhibited melanoma cells growth with IC50 in the low nanomolar range. The compounds are promising drug candidates and convenient tools for solving mechanisms of Hedgehog signaling.

Optimization of Naphthalimide-imidazoacridone with Potent Antitumor Activity Leading to Clinical Candidate (HKH40A, RTA 502)

Journal of Medicinal Chemistry, 2007

Unsymmetrical bifunctional antitumor agent WMC79 was further optimized to generate compound 7b th... more Unsymmetrical bifunctional antitumor agent WMC79 was further optimized to generate compound 7b that not only inhibited the growth of many tumor cell lines, but caused rapid apoptosis. Unlike the parent compound, 7b is toxic to both p53 positive and negative cancer cells. It has potent in vivo activity against xenografts of human colon and pancreatic tumors in athymic mice.

Visualization of G Protein-coupled Receptor Trafficking with the Aid of the Green Fluorescent Protein. ENDOCYTOSIS AND RECYCLING OF CHOLECYSTOKININ RECEPTOR TYPE A

Journal of Biological Chemistry, 1997

A chimeric protein consisting of the cholecystokinin receptor type A (CCKAR) and the green fluore... more A chimeric protein consisting of the cholecystokinin receptor type A (CCKAR) and the green fluorescent protein (GFP) was used for studying receptor localization, internalization, and recycling in live cells in real time in four different cell lines. Fusion of the C terminus of the CCKAR to the N terminus of the GFP did not alter receptor ligand binding affinity, signal transduction, or the pattern of receptor surface expression and receptormediated cholecystokinin (CCK) internalization. The use of a new GFP mutant with increased fluorescence allowed the continuous observation of CCKAR-GFP in stably expressing cell lines. Newly obtained biologically active fluorescent derivatives of CCK were used for simultaneous observation of receptor and ligand trafficking in CHO, NIH/3T3, and HeLa cells stably expressing the fluorescent CCKAR and in transiently transfected COS-1 cells. Receptor internalization was predominantly ligand dependent in HeLa, COS-1, and CHO cells, but was mostly constitutive in NIH/3T3 cells, suggesting the existence of cell-specific regulation of receptor internalization. The CCKAR antagonists, L-364,718 and CCK 27-32 amide potently inhibited spontaneous internalization of the receptor. The average sorting time of CCK and the receptor in the endosomes was about 25 min. The receptor recycled back to the cell membrane with an average time of 60 min. While the ligands sorted to lysosomes, no receptor molecules could be detected there, and no receptor degradation was observed during recycling. These results demonstrate the usefulness of GFP tagging for real time imaging of G protein-coupled receptor trafficking in living cells and suggest that this technique may be successfully applied to the study of the regulation and trafficking mechanisms of other receptors.

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Mechanisms of unphosphorylated STAT3 transcription factor binding to DNA

by Nadya Tarasova, Sergey Chasovskikh, Anatoly Dritschilo, and Valeriy Korostyshevskiy

The Journal of biological chemistry, Jan 20, 2012

Phosphorylation of signal transducer and activator of transcription 3 (STAT3) on a single tyrosin... more Phosphorylation of signal transducer and activator of transcription 3 (STAT3) on a single tyrosine residue in response to growth factors, cytokines, interferons, and oncogenes activates its dimerization, translocation to the nucleus, binding to the interferon γ (gamma)-activated sequence (GAS) DNA-binding site and activation of transcription of target genes. STAT3 is constitutively phosphorylated in various cancers and drives gene expression from GAS-containing promoters to promote tumorigenesis. Recently, roles for unphosphorylated STAT3 (U-STAT3) have been described in response to cytokine stimulation, in cancers, and in maintenance of heterochromatin stability. However, the mechanisms underlying U-STAT3 binding to DNA has not been fully investigated. Here, we explore STAT3-DNA interactions by atomic force microscopy (AFM) imaging. We observed that U-STAT3 molecules bind to the GAS DNA-binding site as dimers and monomers. In addition, we observed that U-STAT3 binds to AT-rich DNA ...

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Deletion of functional gastrin gene markedly increases colon carcinogenesis in response to azoxymethane in mice

by Randall Given and Nadya Tarasova

Gastroenterology, 2002

We recently reported that transgenic mice overexpressing progastrin were at a higher risk for dev... more We recently reported that transgenic mice overexpressing progastrin were at a higher risk for developing colon cancers in response to azoxymethane (AOM), whereas mice overexpressing gastrin-17 were at a reduced risk. To examine further the role of gastrins in colon carcinogenesis, we generated gastrin gene knockout mice (GAS-KO). Methods: The height and proliferative index (PI) of colonic crypts were similar in GAS-KO and wild-type (WT) mice, suggesting that the absence of gastrins in GAS-KO mice did not significantly affect the growth of colonic mucosa. GAS-KO and WT mice were treated with AOM for 3-4 weeks; control mice received saline. Results: Colonic proliferation in response to AOM was significantly increased in GAS-KO vs. WT mice. Aberrant crypt foci (ACFs) were similarly increased significantly by ϳ2-5fold in GAS-KO vs. WT mice after 2 weeks of AOM treatment. Female GAS-KO mice developed adenomas (Ads) and adenocarcinomas (AdCAs) at earlier times (ϳ10 months) than the male GAS-KO mice and the male and female WT mice (ϳ12 months). The total numbers of Ads and AdCAs were significantly higher in GAS-KO than in WT mice. Conclusions: These results suggest the novel possibility that loss of gastrin expression (and hence amidated gastrins) significantly increases susceptibility to colon carcinogenesis in response to AOM. Previous studies with FVB/N transgenic mice similarly suggested a protective role of amidated gastrins against colon carcinogenesis, which supports the present findings of an increase in colon carcinogenesis in GAS-KO mice lacking normal physiological levels of amidated gastrins.

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Distribution and Localization of a Novel Cholecystokinin-Releasing Factor in the Rat Gastrointestinal Tract 1

Endocrinology, 1997

The purpose of this study was to examine the distribution and localization of an intestinal chole... more The purpose of this study was to examine the distribution and localization of an intestinal cholecystokinin (CCK)-releasing factor, called luminal CCK-releasing factor (LCRF), in the gastrointestinal tract and pancreas of the rat. RIA analysis indicates that LCRF immunoreactivity is found throughout the gut including the pancreas, stomach, duodenum, jejunum, ileum, and colon with the highest levels in the small intestine. Immunohistochemistry analysis shows LCRF immunoreactivity staining in intestinal villi, Brunner's glands of the duodenum, the duodenal myenteric plexus, gastric pits, pancreatic ductules, and pancreatic islets. These results indicate potential sources for secretagogue-stimulated release of luminal LCRF and support the hypothesis that LCRF is secreted into the intestinal lumen to stimulate CCK release from mucosal CCK cells. (Endocrinology 138: 5550 -5554, 1997) C HOLECYSTOKININ (CCK) is a major gut hormone involved in the regulation of gallbladder contraction, pancreatic secretion, gastric emptying, bowel motility, satiety, and release of peptide YY from the lower intestine (1, 2). CCK is found in mucosal enteroendocrine cells of the upper small intestine and is secreted into the systemic circulation primarily by ingestion of fats and proteins (1, 3, 4). The exact mechanisms controlling release of CCK into the bloodstream are not clear.

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Wnt4 induces nephronic tubules in metanephric mesenchyme by a non-canonical mechanism

Developmental Biology, 2011

Wnt4 and β-catenin are both required for nephrogenesis, but studies using TCF-reporter mice sugge... more Wnt4 and β-catenin are both required for nephrogenesis, but studies using TCF-reporter mice suggest that canonical Wnt signaling is not activated in metanephric mesenchyme (MM) during its conversion to the epithelia of the nephron. To better define the role of Wnt signaling, we treated rat metanephric mesenchymal progenitors directly with recombinant Wnt proteins. These studies revealed that Wnt4 protein, which is required for nephron formation, induces tubule formation and differentiation markers Lim1 and E-cadherin in MM cells, but does not activate a TCF reporter or up regulate expression of canonical Wnt target gene Axin-2 and has little effect on the stabilization of β-catenin or phosphorylation of disheveled-2. Furthermore, Wnt4 causes membrane localization of ZO-1 and occludin in tight junctions. To directly examine the role of β-catenin/TCF-dependent transcription, we developed synthetic cell-permeable analogs of β-catenin's helix C, which is required for transcriptional activation, in efforts to specifically inhibit canonical Wnt signaling. One inhibitor blocked TCF-dependent transcription and induced degradation of β-catenin but did not affect tubule formation and stimulated the expression of Lim1 and E-cadherin. Since a canonical mechanism appears not to be operative in tubule formation, we assessed the involvement of the non-canonical Ca 2+ -dependent pathway. Treatment of MM cells with Wnt4 induced an influx of Ca 2+ and caused phosphorylation of CaMKII. Moreover, Ionomycin, a Ca 2+dependent pathway activator, stimulated tubule formation. These results demonstrate that the canonical Wnt pathway is not responsible for mesenchymal-epithelial transition (MET) in nephron formation and suggest that the non-canonical calcium/Wnt pathway mediates Wnt4-induced tubulogenesis in the kidney.

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Synthesis and biological activity of 5-aza-ellipticine derivatives

Bioorganic & Medicinal Chemistry Letters, 2007

Novel 5-aza-ellipticine derivatives were synthesized and tested as antitumor agents. The new comp... more Novel 5-aza-ellipticine derivatives were synthesized and tested as antitumor agents. The new compounds were prepared more readily than the analogous ellipticine derivatives, which are known to be potent anti-tumor agents Although the novel 5-aza-ellipticine derivatives are not as biologically active as their corresponding ellipticine analogues, the new compounds represent a new, readily accessible class of heteroaromatic catalytic inhibitors of topoisomerase II and possible anti-tumor agents.

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Anti-peptide antibodies specific for the gastrin/cholecystokinin-B receptor

Letters in Peptide …, 1995

... Tarasova a&#x27;*, Terry D. Copeland b, David W. Farnsworth a, Stephen A. Wank c, Eric A.... more

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