Vadim Gladyshev, PhD

Brigham And Women's Hospital

Brigham And Women's Hospital
Phone: (617) 525-5122
Fax: (617) 525-5147

Vadim Gladyshev, PhD

Brigham And Women's Hospital


  • Professor, Medicine, Harvard Medical School
  • Director of Redox Medicine, Medicine, Brigham And Women's Hospital


Research Abstract

Gladyshev Laboratory – Brigham & Women’s Hospital

The Gladyshev lab research interests focus on redox biology and trace elements as applied to cancer, aging and male reproduction. They are trying to understand the mechanisms of redox regulation of cellular processes by studying reactive oxygen species (ROS) and thiol oxidoreductase functions of cellular components. Little is known of what the specific targets of ROS are and how oxidant and antioxidant signals are transmitted in the cell. To understand mechanisms of redox control, the Gladysehv lab needs to know the identities and functions of most of the participants in the redox process. Thus, they are developing and employing various bioinformatics approaches and carrying out genome sequencing, proteomics and functional genomics studies, which are followed with in vitro and in vivo tests of the identified targets. They are particularly interested in the redox control that involves specific and stochastic oxidation of cysteine and methionine residues in proteins.

In mammals, major redox systems are dependent on the trace element selenium, which is an essential component of various redox enzymes in thioredoxin, glutathione and methionine sulfoxide reduction pathways. Selenium is present in proteins in the form of the 21st amino acid, selenocysteine, encoded by UGA codon. Selenocysteine can be viewed as redox super-cysteine because it is only used as the catalytic residue in oxidoreductases. Because UGA is also a stop signal, selenoprotein genes are typically misannotated in sequence databases. To overcome this problem, they identify these genes by genome-wide searches for structural and thermodynamic properties of specific RNA structures and independently by searches for selenocysteine/cysteine pairs in homologous sequences. Subsequently, the Gladyshev lab characterizes functions, regulation and specific targets of selenoproteins and other oxidoreductases to gain a system-wide view on selenium metabolism and redox regulation of cellular processes.

The Gladyshev lab is expanding their research on the basic mechanisms of aging, which they characterize using methods of biochemistry and bioinformatics and utilizing model organisms, primarily yeast and fruit flies. They also characterize the methionine sulfoxide reductase system, which is a protein and metabolite repair system. More generally, they think aging is the consequence of accumulation of damaged biomolecules in cells and organisms. Therefore, understanding the mechanisms by which organisms deal with damage accumulation and how these processes themselves deteriorate is crucial to an understanding of the aging process.

The lab also studies the 15 kDa selenoprotein (Sep15), which is involved in the quality control of protein folding in the endoplasmic reticulum. They identified Sep15 as a candidate protein that mediates the cancer chemopreventive effect of selenium. The lab is characterizing its function and role in cancer prevention to identify a mechanism by which dietary selenium decreases cancer incidence. Another project involves functional characterization of animal thioredoxin reductases. Mammals have three (cytosolic, mitochondrial and spermatid-specific) thioredoxin reductases; each of them occurs in multiple forms generated by alternative first exon splicing. The Gladyshev lab identified one of them as thioredoxin-glutathione reductase, which is involved in male reproduction.

The Gladyshev lab hopes that their studies will provide a better understanding of the role of redox processes in physiological and pathophysiological states, particularly with regard to aging, cancer, and male reproduction, and will lead to new therapeutic and disease-preventive agents.


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  • Gould NS, Evans P, Martínez-Acedo P, Marino SM, Gladyshev VN, Carroll KS, Ischiropoulos H. Site-Specific Proteomic Mapping Identifies Selectively Modified Regulatory Cysteine Residues in Functionally Distinct Protein Networks. Chem Biol 2015. PubMed
  • Kim MJ, Lee BC, Hwang KY, Gladyshev VN, Kim HY. Selenium utilization in thioredoxin and catalytic advantage provided by selenocysteine. Biochem Biophys Res Commun 2015; 461:648-52. PubMed
  • MacRae SL, Zhang Q, Lemetre C, Seim I, Calder RB, Hoeijmakers J, Suh Y, Gladyshev VN, Seluanov A, Gorbunova V, Vijg J, Zhang ZD. Comparative analysis of genome maintenance genes in naked mole rat, mouse, and human. Aging Cell 2015; 14:288-91. PubMed
  • Nakao LS, Everley RA, Marino SM, Lo SM, de Souza LE, Gygi SP, Gladyshev VN. Mechanism-based Proteomic Screening Identifies Targets of Thioredoxin-like Proteins. J Biol Chem 2015; 290:5685-95. PubMed
  • Bang J, Huh JH, Na JW, Lu Q, Carlson BA, Tobe R, Tsuji PA, Gladyshev VN, Hatfield DL, Lee BJ. Cell Proliferation and Motility are Inhibited by G1 Phase Arrest in 15-kDa Selenoprotein-Deficient Chang Liver Cells. Mol Cells 2015. PubMed
  • Kaya A, Lobanov AV, Gladyshev VN. Evidence that mutation accumulation does not cause aging in Saccharomyces cerevisiae. Aging Cell 2015. PubMed
  • Fushan AA, Turanov AA, Lee SG, Kim EB, Lobanov AV, Yim SH, Buffenstein R, Lee SR, Chang KT, Rhee H, Kim JS, Yang KS, Gladyshev VN. Gene expression defines natural changes in mammalian lifespan. Aging Cell 2015. PubMed
  • Tian X, Azpurua J, Ke Z, Augereau A, Zhang ZD, Vijg J, Gladyshev VN, Gorbunova V, Seluanov A. INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform. Proc Natl Acad Sci U S A 2015; 112:1053-8. PubMed
  • Bang J, Jang M, Huh JH, Na JW, Shim M, Carlson BA, Tobe R, Tsuji PA, Gladyshev VN, Hatfield DL, Lee BJ. Deficiency of the 15-kDa selenoprotein led to cytoskeleton remodeling and non-apoptotic membrane blebbing through a RhoA/ROCK pathway. Biochem Biophys Res Commun 2015; 456:884-90. PubMed
  • Tsuji PA, Carlson BA, Yoo MH, Naranjo-Suarez S, Xu XM, He Y, Asaki E, Seifried HE, Reinhold WC, Davis CD, Gladyshev VN, Hatfield DL. The 15kDa selenoprotein and thioredoxin reductase 1 promote colon cancer by different pathways. PLoS ONE 2015; 10:e0124487. PubMed
  • Gerashchenko MV, Gladyshev VN. Translation inhibitors cause abnormalities in ribosome profiling experiments. Nucleic Acids Res 2014; 42:e134. PubMed
  • Guo C, Chen X, Song H, Maynard MA, Zhou Y, Lobanov AV, Gladyshev VN, Ganis JJ, Wiley D, Jugo RH, Lee NY, Castroneves LA, Zon LI, Scanlan TS, Feldman HA, Huang SA. Intrinsic expression of a multiexon type 3 deiodinase gene controls zebrafish embryo size. Endocrinology 2014; 155:4069-80. PubMed
  • Turanov AA, Shchedrina VA, Everley RA, Lobanov AV, Yim SH, Marino SM, Gygi SP, Hatfield DL, Gladyshev VN. Selenoprotein S is Involved in Maintenance and Transport of Multiprotein Complexes. Biochem J 2014. PubMed
  • Barroso M, Florindo C, Kalwa H, Silva Z, Turanov AA, Carlson BA, Tavares de Almeida I, Blom HJ, Gladyshev VN, Hatfield DL, Michel T, Castro R, Loscalzo J, Handy DE. Inhibition of Cellular Methyltransferases Promotes Endothelial Cell Activation by Suppressing Glutathione Peroxidase-1 Expression. J Biol Chem 2014. PubMed
  • Hatfield DL, Tsuji PA, Carlson BA, Gladyshev VN. Selenium and selenocysteine: roles in cancer, health, and development. Trends Biochem Sci 2014; 39:112-20. PubMed
  • Malinouski M, Hasan NM, Zhang Y, Seravalli J, Lin J, Avanesov A, Lutsenko S, Gladyshev VN. Genome-wide RNAi ionomics screen reveals new genes and regulation of human trace element metabolism. Nat Commun 2014; 5:3301. PubMed
  • Lee BC, Kaya A, Ma S, Kim G, Gerashchenko MV, Yim SH, Hu Z, Harshman LG, Gladyshev VN. Methionine restriction extends lifespan of Drosophila melanogaster under conditions of low amino-acid status. Nat Commun 2014; 5:3592. PubMed
  • Labunskyy VM, Gerashchenko MV, Delaney JR, Kaya A, Kennedy BK, Kaeberlein M, Gladyshev VN. Lifespan extension conferred by endoplasmic reticulum secretory pathway deficiency requires induction of the unfolded protein response. PLoS Genet. 2014; 10:e1004019. PubMed
  • Avanesov AS, Ma S, Pierce KA, Yim SH, Lee BC, Clish CB, Gladyshev VN. Age- and diet-associated metabolome remodeling characterizes the aging process driven by damage accumulation. Elife 2014; 3:e02077. PubMed
  • Romagné F, Santesmasses D, White L, Sarangi GK, Mariotti M, Hübler R, Weihmann A, Parra G, Gladyshev VN, Guigó R, Castellano S. SelenoDB 2.0: annotation of selenoprotein genes in animals and their genetic diversity in humans. Nucleic Acids Res 2013; 42:D437-43. PubMed
  • Han SJ, Lee BC, Yim SH, Gladyshev VN, Lee SR. Characterization of Mammalian selenoprotein o: a redox-active mitochondrial protein. PLoS ONE 2014; 9:e95518. PubMed
  • Turanov AA, Lobanov AV, Hatfield DL, Gladyshev VN. UGA codon position-dependent incorporation of selenocysteine into mammalian selenoproteins. Nucleic Acids Res 2013; 41:6952-9. PubMed
  • Naranjo-Suarez S, Carlson BA, Tobe R, Yoo MH, Tsuji PA, Gladyshev VN, Hatfield DL. Regulation of HIF-1留 activity by overexpression of thioredoxin is independent of thioredoxin reductase status. Mol Cells 2013; 36:151-7. PubMed
  • Kasaikina MV, Turanov AA, Avanesov A, Schweizer U, Seeher S, Bronson RT, Novoselov SN, Carlson BA, Hatfield DL, Gladyshev VN. Contrasting roles of dietary selenium and selenoproteins in chemically induced hepatocarcinogenesis. Carcinogenesis 2013. PubMed
  • Yoo MH, Carlson BA, Gladyshev VN, Hatfield DL. Abrogated thioredoxin system causes increased sensitivity to TNF-留-induced apoptosis via enrichment of p-ERK 1/2 in the nucleus. PLoS ONE 2013; 8:e71427. PubMed
  • Gladyshev VN. On the cause of aging and control of lifespan: Heterogeneity leads to inevitable damage accumulation, causing aging; Control of damage composition and rate of accumulation define lifespan. Bioessays 2012; 34:925-9. PubMed
  • Gerashchenko MV, Lobanov AV, Gladyshev VN. Genome-wide ribosome profiling reveals complex translational regulation in response to oxidative stress. Proc Natl Acad Sci U S A 2012; 109:17394-9. PubMed
  • Labunskyy VM, Gladyshev VN. Role of Reactive Oxygen Species-Mediated Signaling in Aging. Antioxid Redox Signal 2012. PubMed
  • Carlson BA, Yoo MH, Tobe R, Mueller C, Naranjo-Suarez S, Hoffmann VJ, Gladyshev VN, Hatfield DL. Thioredoxin reductase 1 protects against chemically induced hepatocarcinogenesis via control of cellular redox homeostasis. Carcinogenesis 2012; 33:1806-13. PubMed
  • Tobe R, Yoo MH, Fradejas N, Carlson BA, Calvo S, Gladyshev VN, Hatfield DL. Thioredoxin reductase 1 deficiency enhances selenite toxicity in cancer cells via a thioredoxin-independent mechanism. Biochem J 2012; 445:423-30. PubMed
  • Wu C, Parrott AM, Fu C, Liu T, Marino SM, Gladyshev VN, Jain MR, Baykal AT, Li Q, Oka S, Sadoshima J, Beuve A, Simmons WJ, Li H. Thioredoxin 1-Mediated Post-Translational Modifications: Reduction, Transnitrosylation, Denitrosylation and Related Proteomics Methodologies. Antioxid Redox Signal 2011. PubMed
  • Lee BC, Lobanov AV, Marino SM, Kaya A, Seravalli J, Hatfield DL, Gladyshev VN. A four selenocysteine, two SECIS element methionine sulfoxide reductase from Metridium senile reveals a non-catalytic function of selenocysteines. J Biol Chem 2011. PubMed
  • Kasaikina MV, Lobanov AV, Malinouski MY, Lee BC, Seravalli J, Fomenko DE, Turanov AA, Finney L, Vogt S, Park TJ, Miller RA, Hatfield DL, Gladyshev VN. Reduced utilization of selenium by naked mole rats due to a specific defect in GPx1 expression. J Biol Chem 2011. PubMed
  • Kim MJ, Lee BC, Jeong J, Lee KJ, Hwang KY, Gladyshev VN, Kim HY. Tandem use of selenocysteine: adaptation of a selenoprotein glutaredoxin for reduction of selenoprotein methionine sulfoxide reductase. Mol Microbiol 2011; 79:1194-203. PubMed
  • Fomenko DE, Koc A, Agisheva N, Jacobsen M, Kaya A, Malinouski M, Rutherford JC, Siu KL, Jin DY, Winge DR, Gladyshev VN. Thiol peroxidases mediate specific genome-wide regulation of gene expression in response to hydrogen peroxide. Proc Natl Acad Sci U S A 2011; 108:2729-34. PubMed
  • Suzuki Y, St Onge RP, Mani R, King OD, Heilbut A, Labunskyy VM, Chen W, Pham L, Zhang LV, Tong AH, Nislow C, Giaever G, Gladyshev VN, Vidal M, Schow P, Lehár J, Roth FP. Knocking out multigene redundancies via cycles of sexual assortment and fluorescence selection. Nat Methods 2011; 8:159-64. PubMed
  • Marino SM, Gladyshev VN. Proteomics: mapping reactive cysteines. Nat Chem Biol 2011; 7:72-3. PubMed
  • Lee BC, Gladyshev VN. The biological significance of methionine sulfoxide stereochemistry. Free Radic Biol Med 2011; 50:221-7. PubMed
  • Malinouski M, Zhou Y, Belousov VV, Hatfield DL, Gladyshev VN. Hydrogen peroxide probes directed to different cellular compartments. PLoS ONE 2011; 6:e14564. PubMed
  • Marino SM, Gladyshev VN. Cysteine Function Governs Its Conservation and Degeneration and Restricts Its Utilization on Protein Surfaces. J Mol Biol 2010; 404:902-16. PubMed
  • Xu XM, Turanov AA, Carlson BA, Yoo MH, Everley RA, Nandakumar R, Sorokina I, Gygi SP, Gladyshev VN, Hatfield DL. Targeted insertion of cysteine by decoding UGA codons with mammalian selenocysteine machinery. Proc Natl Acad Sci U S A 2011; 107:21430-4. PubMed
  • Aachmann FL, Sal LS, Kim HY, Marino SM, Gladyshev VN, Dikiy A. Insights into function, catalytic mechanism, and fold evolution of selenoprotein methionine sulfoxide reductase B1 through structural analysis. J Biol Chem 2010; 285:33315-23. PubMed
  • Kaya A, Koc A, Lee BC, Fomenko DE, Rederstorff M, Krol A, Lescure A, Gladyshev VN. Compartmentalization and Regulation of Mitochondrial Function by Methionine Sulfoxide Reductases in Yeast. Biochemistry 2010; 49:8618-25. PubMed
  • Marino SM, Li Y, Fomenko DE, Agisheva N, Cerny RL, Gladyshev VN. Characterization of surface-exposed reactive cysteine residues in Saccharomyces cerevisiae. Biochemistry 2010; 49:7709-21. PubMed
  • Marino SM, Gladyshev V. Redox Biology: Computational Approaches to the Investigation of Functional Cysteine Residues. Antioxid Redox Signal 2010. PubMed
  • Turanov AA, Kehr S, Marino SM, Yoo MH, Carlson BA, Hatfield DL, Gladyshev VN. Mammalian thioredoxin reductase 1: roles in redox homoeostasis and characterization of cellular targets. Biochem J 2010; 430:285-93. PubMed
  • Lobanov AV, Turanov AA, Hatfield DL, Gladyshev VN. Dual functions of codons in the genetic code. Crit Rev Biochem Mol Biol 2010; 45:257-65. PubMed
  • Carlson BA, Yoo MH, Shrimali RK, Irons R, Gladyshev VN, Hatfield DL, Park JM. Role of selenium-containing proteins in T-cell and macrophage function. Proc Nutr Soc 2010; 69:300-10. PubMed
  • Irons R, Tsuji PA, Carlson BA, Ouyang P, Yoo MH, Xu XM, Hatfield DL, Gladyshev VN, Davis CD. Deficiency in the 15-kDa selenoprotein inhibits tumorigenicity and metastasis of colon cancer cells. Cancer Prev Res (Phila Pa) 2010; 3:630-9. PubMed
  • Shchedrina VA, Zhang Y, Labunskyy VM, Hatfield DL, Gladyshev VN. Structure-function relations, physiological roles, and evolution of mammalian ER-resident selenoproteins. Antioxid Redox Signal 2010; 12:839-49. PubMed
  • Yoo MH, Gu X, Xu XM, Kim JY, Carlson BA, Patterson AD, Cai H, Gladyshev VN, Hatfield DL. Delineating the role of glutathione peroxidase 4 in protecting cells against lipid hydroperoxide damage and in Alzheimer's disease. Antioxid Redox Signal 2010; 12:819-27. PubMed
  • Novoselov SV, Kim HY, Hua D, Lee BC, Astle CM, Harrison DE, Friguet B, Moustafa ME, Carlson BA, Hatfield DL, Gladyshev VN. Regulation of selenoproteins and methionine sulfoxide reductases A and B1 by age, calorie restriction, and dietary selenium in mice. Antioxid Redox Signal 2010; 12:829-38. PubMed
  • Zhang Y, Gladyshev VN. dbTEU: a protein database of trace element utilization. Bioinformatics 2010; 26:700-2. PubMed
  • Gerashchenko MV, Su D, Gladyshev VN. CUG start codon generates thioredoxin/glutathione reductase isoforms in mouse testes. J Biol Chem 2010; 285:4595-602. PubMed
  • Zhang Y, Gladyshev VN. General trends in trace element utilization revealed by comparative genomic analyses of Co, Cu, Mo, Ni, and Se. J Biol Chem 2010; 285:3393-405. PubMed
  • Marino SM, Gladyshev VN. Structural analysis of cysteine S-nitrosylation: a modified acid-based motif and the emerging role of trans-nitrosylation. J Mol Biol 2010; 395:844-59. PubMed
  • Bekaert M, Firth AE, Zhang Y, Gladyshev VN, Atkins JF, Baranov PV. Recode-2: new design, new search tools, and many more genes. Nucleic Acids Res 2009; 38:D69-74. PubMed
  • Sengupta A, Lichti UF, Carlson BA, Ryscavage AO, Gladyshev VN, Yuspa SH, Hatfield DL. Selenoproteins are essential for proper keratinocyte function and skin development. PLoS ONE 2010; 5:e12249. PubMed
  • Yoo MH, Carlson BA, Tsuji P, Irons R, Gladyshev VN, Hatfield DL. Alteration of thioredoxin reductase 1 levels in elucidating cancer etiology. Methods Enzymol 2010; 474:255-75. PubMed
  • Liang X, Fomenko DE, Hua D, Kaya A, Gladyshev VN. Diversity of protein and mRNA forms of mammalian methionine sulfoxide reductase B1 due to intronization and protein processing. PLoS ONE 2010; 5:e11497. PubMed
  • Turanov AA, Hatfield DL, Gladyshev VN. Characterization of protein targets of mammalian thioredoxin reductases. Methods Enzymol 2010; 474:245-54. PubMed
  • Sengupta A, Carlson BA, Labunskyy VM, Gladyshev VN, Hatfield DL. Selenoprotein T deficiency alters cell adhesion and elevates selenoprotein W expression in murine fibroblast cells. Biochem. Cell Biol. 2009; 87:953-61. PubMed
  • Lee BC, Dikiy A, Kim HY, Gladyshev VN. Functions and evolution of selenoprotein methionine sulfoxide reductases. Biochim Biophys Acta 2009; 1790:1471-7. PubMed
  • Hatfield DL, Yoo MH, Carlson BA, Gladyshev VN. Selenoproteins that function in cancer prevention and promotion. Biochim Biophys Acta 2009; 1790:1541-5. PubMed
  • Lobanov AV, Hatfield DL, Gladyshev VN. Eukaryotic selenoproteins and selenoproteomes. Biochim Biophys Acta 2009; 1790:1424-8. PubMed
  • Jin BY, Sartoretto JL, Gladyshev VN, Michel T. Endothelial nitric oxide synthase negatively regulates hydrogen peroxide-stimulated AMP-activated protein kinase in endothelial cells. Proc Natl Acad Sci U S A 2009; 106:17343-8. PubMed
  • Zhang Y, Gladyshev VN. Comparative genomics of trace elements: emerging dynamic view of trace element utilization and function. Chem. Rev. 2009; 109:4828-61. PubMed
  • Labunskyy VM, Yoo MH, Hatfield DL, Gladyshev VN. Sep15, a thioredoxin-like selenoprotein, is involved in the unfolded protein response and differentially regulated by adaptive and acute ER stresses. Biochemistry 2009; 48:8458-65. PubMed
  • Kaya A, Karakaya HC, Fomenko DE, Gladyshev VN, Koc A. Identification of a novel system for boron transport: Atr1 is a main boron exporter in yeast. Mol Cell Biol 2009; 29:3665-74. PubMed
  • Xu XM, Yoo MH, Carlson BA, Gladyshev VN, Hatfield DL. Simultaneous knockdown of the expression of two genes using multiple shRNAs and subsequent knock-in of their expression. Nat Protoc 2009; 4:1338-48. PubMed
  • Carlson BA, Yoo MH, Sano Y, Sengupta A, Kim JY, Irons R, Gladyshev VN, Hatfield DL, Park JM. Selenoproteins regulate macrophage invasiveness and extracellular matrix-related gene expression. BMC Immunol 2009; 10:57. PubMed
  • Carlson BA, Yoo MH, Tsuji PA, Gladyshev VN, Hatfield DL. Mouse models targeting selenocysteine tRNA expression for elucidating the role of selenoproteins in health and development. Molecules 2009; 14:3509-27. PubMed
  • Turanov A.A., Lobanov A.V., Fomenko D.E., Morrison H.G., Sogin M.L., Klobutcher L.A., Hatfield D.L., Gladyshev V.N. . Genetic code supports targeted insertion of two amino acids by one codon Science 2009; 323:259-261.
  • Fomenko, D. E., Xing, W., Adair, B. M., Thomas, D. J., and Gladyshev, V. N. . High-throughput identification of catalytic redox-active cysteine residues Science 2007; 135:387-389.
  • Hacioglu E, Esmer I, Fomenko DE, Gladyshev VN, Koc A. The roles of thiol oxidoreductases in yeast replicative aging. Mech Ageing Dev 2010; 131:692-9. PubMed