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Dive into the research topics where Vasily A. Yakovlev is active.

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Featured researches published by Vasily A. Yakovlev.


Biochemistry | 2010

Nitration of the Tumor Suppressor Protein p53 at Tyrosine 327 Promotes p53 Oligomerization and Activation

Vasily A. Yakovlev; Alexander S. Bayden; Paul R. Graves; Glen E. Kellogg; Ross B. Mikkelsen

Previous studies demonstrate that nitric oxide (NO) promotes p53 transcriptional activity by a classical DNA damage responsive mechanism involving activation of ATM/ATR and phosphorylation of p53. These studies intentionally used high doses of NO donors to achieve the maximum DNA damage. However, lower concentrations of NO donors also stimulate rapid and unequivocal nuclear retention of p53 but apparently do not require ATM/ATR-dependent p53 phosphorylation or total p53 protein accumulation. To identify possible mechanisms for p53 activation at low NO levels, the role of Tyr nitration in p53 activation was evaluated. Low concentrations of the NO donor, DETA NONOate (<200 microM), exclusively nitrate Tyr327 within the tetramerization domain promoting p53 oligomerization, nuclear accumulation, and increased DNA-binding activity without p53 Ser15 phosphorylation. Molecular modeling indicates that nitration of one Tyr327 stabilizes the dimer by about 2.67 kcal mol(-1). Significant quantitative and qualitative differences in the patterns of p53-target gene modulation by low (50 microM), non-DNA-damaging and high (500 microM), DNA-damaging NO donor concentrations were shown. These results demonstrate a new posttranslational mechanism for modulating p53 transcriptional activity responsive to low NO concentrations and independent of DNA damage signaling.


Journal of Receptors and Signal Transduction | 2010

Protein tyrosine nitration in cellular signal transduction pathways

Vasily A. Yakovlev; Ross B. Mikkelsen

How specificity and reversibility in tyrosine nitration are defined biologically in cellular systems is poorly understood. As more investigations identify proteins involved in cell regulatory pathways in which only a small fraction of that protein pool is modified by nitration to affect cell function, the mechanisms of biological specificity and reversal should come into focus. In this review experimental evidence has been summarized to suggest that tyrosine nitration is a highly selective modification and under certain physiological conditions fulfills the criteria of a physiologically relevant signal. It can be specific, reversible, occurs on a physiological time scale, and, depending on a target, can result in either activation or inhibition.


Free Radical Biology and Medicine | 2011

Factors influencing protein tyrosine nitration--structure-based predictive models.

Alexander S. Bayden; Vasily A. Yakovlev; Paul R. Graves; Ross B. Mikkelsen; Glen E. Kellogg

Models for exploring tyrosine nitration in proteins have been created based on 3D structural features of 20 proteins for which high-resolution X-ray crystallographic or NMR data are available and for which nitration of 35 total tyrosines has been experimentally proven under oxidative stress. Factors suggested in previous work to enhance nitration were examined with quantitative structural descriptors. The role of neighboring acidic and basic residues is complex: for the majority of tyrosines that are nitrated the distance to the heteroatom of the closest charged side chain corresponds to the distance needed for suspected nitrating species to form hydrogen bond bridges between the tyrosine and that charged amino acid. This suggests that such bridges play a very important role in tyrosine nitration. Nitration is generally hindered for tyrosines that are buried and for those tyrosines for which there is insufficient space for the nitro group. For in vitro nitration, closed environments with nearby heteroatoms or unsaturated centers that can stabilize radicals are somewhat favored. Four quantitative structure-based models, depending on the conditions of nitration, have been developed for predicting site-specific tyrosine nitration. The best model, relevant for both in vitro and in vivo cases, predicts 30 of 35 tyrosine nitrations (positive predictive value) and has a sensitivity of 60/71 (11 false positives).


Cancer Research | 2013

Nitric Oxide–Dependent Downregulation of BRCA1 Expression Promotes Genetic Instability

Vasily A. Yakovlev

Elevated levels of nitric oxide (NO) and reactive nitrogen species (RNS) may link inflammation to the initiation, promotion, and progression of cancer. Traditionally, this link has been thought to be mediated by the effects of NO/RNS in generating DNA damage. However, this damage also stimulates DNA repair responses with subsequent blocks to cell proliferation and apoptosis, thereby preventing accumulation of NO/RNS-generated mutations. In addressing this conundrum, I describe here an alternative mechanism for understanding mutagenesis by NO/RNS. Moderate NO/RNS concentrations stimulated mutagenesis not directly by generating DNA damage but indirectly by modifying the activities of DNA repair and genome stability factors without affecting cell proliferation. NO/RNS at concentrations physiologically relevant to inflammation stimulated PP2A activity, leading to dephosphorylation of RBL2, its accumulation in the nucleus, and formation of RBL2/E2F4 complexes. RBL2/E2F4 formation in turn led to a shift in BRCA1 promoter occupancy from complexes containing activator E2F1 to complexes containing repressor E2F4, downregulating BRCA1 expression. By inhibiting BRCA1 expression, NO/RNS thereby reduces the ability of cells to repair DNA double-strand breaks through homologous recombination repair, increasing the involvement of error-prone nonhomologous end joining (NHEJ). In summary, NO/RNS stimulates genetic instability by inhibiting BRCA1 expression and shifting DNA repair from high fidelity to error-prone mechanisms.


Molecular Cancer Research | 2015

The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression

Christopher S. Rabender; Asim Alam; Gobalakrishnan Sundaresan; Robert J. Cardnell; Vasily A. Yakovlev; Nitai D. Mukhopadhyay; Paul R. Graves; Jamal Zweit; Ross B. Mikkelsen

Here, evidence suggests that nitric oxide synthases (NOS) of tumor cells, in contrast with normal tissues, synthesize predominantly superoxide and peroxynitrite. Based on high-performance liquid chromatography analysis, the underlying mechanism for this uncoupling is a reduced tetrahydrobiopterin:dihydrobiopterin ratio (BH4:BH2) found in breast, colorectal, epidermoid, and head and neck tumors compared with normal tissues. Increasing BH4:BH2 and reconstitution of coupled NOS activity in breast cancer cells with the BH4 salvage pathway precursor, sepiapterin, causes significant shifts in downstream signaling, including increased cGMP-dependent protein kinase (PKG) activity, decreased β-catenin expression, and TCF4 promoter activity, and reduced NF-κB promoter activity. Sepiapterin inhibited breast tumor cell growth in vitro and in vivo as measured by a clonogenic assay, Ki67 staining, and 2[18F]fluoro-2-deoxy-d-glucose–deoxyglucose positron emission tomography (FDG-PET). In summary, using diverse tumor types, it is demonstrated that the BH4:BH2 ratio is lower in tumor tissues and, as a consequence, NOS activity generates more peroxynitrite and superoxide anion than nitric oxide, resulting in important tumor growth–promoting and antiapoptotic signaling properties. Implications: The synthetic BH4, Kuvan, is used to elevate BH4:BH2 in some phenylketonuria patients and to treat diseases associated with endothelial dysfunction, suggesting a novel, testable approach for correcting an abnormality of tumor metabolism to control tumor growth. Mol Cancer Res; 13(6); 1034–43. ©2015 AACR.


International Journal of Radiation Oncology Biology Physics | 2010

Proteomic Analysis of Radiation-Induced Changes in Rat Lung: Modulation by the Superoxide Dismutase Mimetic MnTE-2-PyP5+

Vasily A. Yakovlev; Christopher S. Rabender; Heidi Sankala; Ben Gauter-Fleckenstein; Katharina Fleckenstein; Ines Batinic-Haberle; Isabel L. Jackson; Zeljko Vujaskovic; Mitchell S. Anscher; Ross B. Mikkelsen; Paul R. Graves

PURPOSE To identify temporal changes in protein expression in the irradiated rat lung and generate putative mechanisms underlying the radioprotective effect of the manganese superoxide dismutase mimetic MnTE-2-PyP(5+). METHODS AND MATERIALS Female Fischer 344 rats were irradiated to the right hemithorax with a single dose of 28 Gy and killed from day 1 to 20 weeks after irradiation. Proteomic profiling was performed to identify proteins that underwent significant changes in abundance. Some irradiated rats were administered MnTE-2-PyP(5+) and changes in protein expression and phosphorylation determined at 6 weeks after irradiation. RESULTS Radiation induced a biphasic stress response in the lung, as shown by the induction of heme oxygenase 1 at 1-3 days and at 6-8 weeks after irradiation. At 6-8 weeks after irradiation, the down-regulation of proteins involved in cytoskeletal architecture (filamin A and talin), antioxidant defense (biliverdin reductase and peroxiredoxin II), and cell signaling (β-catenin, annexin II, and Rho-guanosine diphosphate dissociation inhibitor) was observed. Treatment with MnTE-2-PyP(5+) partially prevented the apparent degradation of filamin and talin, reduced the level of cleaved caspases 3 and 9, and promoted Akt phosphorylation as well as β-catenin expression. CONCLUSION A significant down-regulation of proteins and an increase in protein markers of apoptosis were observed at the onset of lung injury in the irradiated rat lung. Treatment with MnTE-2-PyP(5+), which has been demonstrated to reduce lung injury from radiation, reduced apparent protein degradation and apoptosis indicators, suggesting that preservation of lung structural integrity and prevention of cell loss may underlie the radioprotective effect of this compound.


Redox biology | 2015

Role of nitric oxide in the radiation-induced bystander effect

Vasily A. Yakovlev

Cells that are not irradiated but are affected by “stress signal factors” released from irradiated cells are called bystander cells. These cells, as well as directly irradiated ones, express DNA damage-related proteins and display excess DNA damage, chromosome aberrations, mutations, and malignant transformation. This phenomenon has been studied widely in the past 20 years, since its first description by Nagasawa and Little in 1992, and is known as the radiation-induced bystander effect (RIBE). Several factors have been identified as playing a role in the bystander response. This review will focus on one of them, nitric oxide (NO), and its role in the stimulation and propagation of RIBE. The hydrophobic properties of NO, which permit its diffusion through the cytoplasm and plasma membranes, allow this signaling molecule to easily spread from irradiated cells to bystander cells without the involvement of gap junction intercellular communication. NO produced in irradiated tissues mediates cellular regulation through posttranslational modification of a number of regulatory proteins. The best studied of these modifications are S-nitrosylation (reversible oxidation of cysteine) and tyrosine nitration. These modifications can up- or down-regulate the functions of many proteins modulating different NO-dependent effects. These NO-dependent effects include the stimulation of genomic instability (GI) and the accumulation of DNA errors in bystander cells without direct DNA damage.


International Journal of Radiation Oncology Biology Physics | 2015

A Preliminary Study on Racial Differences in HMOX1, NFE2L2, and TGFβ1 Gene Polymorphisms and Radiation-Induced Late Normal Tissue Toxicity

Asim Alam; Nitai D. Mukhopadhyay; Yi Ning; Leonid B. Reshko; Robert J. G. Cardnell; Omair Alam; Christopher S. Rabender; Vasily A. Yakovlev; Linda Walker; Mitchell S. Anscher; Ross B. Mikkelsen

PURPOSE This study tested whether racial differences in genetic polymorphisms of 4 genes involved in wound repair and response to radiation can be used to predict the occurrence of normal tissue late effects of radiation therapy and indicate potential therapeutic targets. METHODS AND MATERIALS This prospective study examined genetic polymorphisms that modulate the expression of 4 genes involved in inflammation and fibrosis and response to radiation (HMOX1, NFE2L2, NOS3, and TGFβ1). DNA from blood samples of 179 patients (∼ 80% breast and head and neck) collected at the time of diagnosis by their radiation oncologist as exhibiting late normal tissue toxicity was used for the analysis. Patient demographics were as follows: 56% white, 43% African American, 1% other. Allelic frequencies of the different polymorphisms of the participants were compared with those of the general American population stratified by race. Twenty-six additional patients treated with radiation, but without toxicity at 3 months or later after therapy, were also analyzed. RESULTS Increased frequency of a long GT repeat in the HMOX1 promoter was associated with late effects in both African American and white populations. The single nucleotide polymorphisms (SNP) rs1800469 in the TGFβ1 promoter and the rs6721961 SNP in the NFE2L2 promoter were also found to significantly associate with late effects in African Americans but not whites. A combined analysis of these polymorphisms revealed that >90% of African American patients with late effects had at least 1 of these minor alleles, and 58% had 2 or more. No statistical significance was found relating the studied NOS3 polymorphisms and normal tissue toxicity. CONCLUSIONS These results support a strong association between wound repair and late toxicities of radiation. The presence of these genetic risk factors can vary significantly among different ethnic groups, as demonstrated for some of the SNPs. Future studies should account for the possibility of such ethnic heterogeneity in the late toxicities of radiation.


Free Radical Biology and Medicine | 2016

Cells redox environment modulates BRCA1 expression and DNA homologous recombination repair

Aaron Wilson; Vasily A. Yakovlev

Cancer development and progression have been linked to oxidative stress, a condition characterized by unbalanced increase in ROS and RNS production. The main endogenous initiators of the redox imbalance in cancer cells are defective mitochondria, elevated NOX activity, and uncoupled NOS3. Traditionally, most attention has been paid to direct oxidative damage to DNA by certain ROS. However, increase in oxidative DNA lesions does not always lead to malignancy. Hence, additional ROS-dependent, pro-carcinogenic mechanisms must be important. Our recent study demonstrated that Tyr nitration of PP2A stimulates its activity and leads to downregulation of BRCA1 expression. This provides a mechanism for chromosomal instability essential for tumor progression. In the present work, we demonstrated that inhibition of ROS production by generating mitochondrial-electron-transport-deficient cell lines (ρ0 cells) or by inhibition of NOX activity with a selective peptide inhibitor significantly reduced PP2A Tyr nitration and its activity in different cancer cell lines. As a result of the decreased PP2A activity, BRCA1 expression was restored along with a significantly enhanced level of DNA HRR. We used TCGA database to analyze the correlation between expressions of the NOX regulatory subunits, NOS isoforms, and BRCA1 in the 3 cancer research studies: breast invasive carcinoma, ovarian cystadenocarcinoma, and lung adenocarcinoma. TCGA database analysis demonstrated that the high expression levels of most of the NOX regulatory subunits responsible for stimulation of NOX1-NOX4 were associated with significant downregulation of BRCA1 expression.


Archive | 2015

Nitric Oxide and Genomic Stability

Vasily A. Yakovlev

Epidemiological evidence accumulating over the years has provided a positive correlation between cancer incidence and chronic inflammation. Regardless of etiology, inflammatory conditions are characterized by overexpression of inducible nitric oxide synthase (iNOS) and overproduction of nitric oxide/reactive nitrogen species (NO/RNS) in epithelial and inflammatory cells at the site of carcinogenesis. NO/RNS produced in infected and inflamed tissues can contribute to the process of carcinogenesis by different mechanisms. In this chapter, we discuss NO/RNS-dependent mechanisms of genomic instability (GI) and bystander effects. We explain the mechanism of “synthetic lethality” of the NO-donor/PARP-inhibitor combination and its role in sensitization of the cancer cells to DNA-damaging agents. We postulate the “mutator field” theory and the definition of mutagenesis efficacy.

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Ross B. Mikkelsen

Virginia Commonwealth University

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Christopher S. Rabender

Virginia Commonwealth University

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Paul R. Graves

Virginia Commonwealth University

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Asim Alam

Virginia Commonwealth University

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Mitchell S. Anscher

Virginia Commonwealth University

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Glen E. Kellogg

Virginia Commonwealth University

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Aaron Wilson

Virginia Commonwealth University

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Alexander S. Bayden

Virginia Commonwealth University

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Igor J. Barani

Virginia Commonwealth University

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