The DOI matches its Crossref record; 60 of the 61 references it cites were found in a registry or an index.
S-Glutathionylation Impairs Signal Transducer and Activator of Transcription 3 Activation and Signaling
Open accessAbstract
S-glutathionylation is a physiological, reversible protein modification of cysteine residues with glutathione in response to mild oxidative stress. Because the key cell growth regulator signal transducer and activator of transcription (STAT) 3 is particularly susceptible to redox regulation, we hypothesized that oxidative modification of cysteine residues of STAT3 by S-glutathionylation may occur. Herein, we show that the cysteine residues of STAT3 are modified by a thiol-alkylating agent and are the targets of S-glutathionylation. STAT3 protein thiol reactivity was reversibly attenuated with concomitant increase in the S-glutathionylation of STAT3 upon treatment of human HepG2 hepatoma cells with pyrrolidine dithiocarbamate, glutathione disulfide, or diamide. Under these conditions there was a marked reduction in IL-6-dependent STAT3 signaling, including decreased STAT3 tyrosine phosphorylation, loss in nuclear accumulation of STAT3, and impaired expression of target genes, such as fibrinogen-γ. In a cell-free system, diamide induced glutathionylation of STAT3, which was decreased upon addition of glutaredoxin (GRX)-1, a deglutathionylation enzyme, or the reducing agent, dithiothreitol. Glutathionylated STAT3 was a poor Janus protein tyrosine kinase 2 substrate in vitro, and it exhibited low DNA-binding activity. Cellular GRX-1 activity was inhibited by diamide and pyrrolidine dithiocarbamate treatment; however, ectopic expression of GRX-1 was accompanied by a modest increase in phosphorylation, nuclear translocation, and DNA-binding ability of STAT3 in response to IL-6. These results are the first to show S-glutathionylation of STAT3, a modification that may exert regulatory function in STAT3 signaling. Reversible S-glutathionylation of STAT3 regulates its activity as transcription factor.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“STAT3 itself can be subject to direct modification by oxidative stress, as 9 of the 14 cysteine residues within STAT3 have been reported to be redox sensitive.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Xie et al., 2009
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“These modifications affect the transcriptional activity of STAT3 through inhibiting Y705 phosphorylation and/or DNA binding, as well as inducing formation of higher order complexes and interfering with the function of the TAD (Li and Shaw, 2004; Xie et al., 2009; Li et al., 2010a; Kurdi et al., 2012; Butturini et al., 2014; Sobotta et al., 2015).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Xie et al., 2009
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“thiol-targeting agents also inhibited IL-6–induced STAT3 activation by S-glutathionylation in HepG2 cells (Xie et al., 2009), human endothelial cells, neonatal rat cardiomyocytes, and adult mouse cardiac myocytes (Zgheib et al., 2012)”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Xie et al., 2009
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Wound healing: an overview of acute, fibrotic and delayed healing
Diegelmann, R. (2004) · Frontiers in Bioscience · doi:10.2741/1184 · Cited by 2,147
INTERLEUKIN-6: From Basic Science to Medicine—40 Years in Immunology
Kishimoto, T. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.23.021704.115806 · Cited by 1,040
Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase
Argetsinger, L. S., Campbell, G. S., Yang, X.-J., Witthuhn, B. A., Silvennoinen, O., Ihle, J. N., & Carter‐Su, C. (1993) · Cell · doi:10.1016/0092-8674(93)90415-m · Cited by 974
The role of IL-6 and STAT3 in inflammation and cancer
Hodge, D. R., Hurt, E. M., & Farrar, W. L. (2005) · European Journal of Cancer · doi:10.1016/j.ejca.2005.08.016 · Cited by 966
The Biotin Switch Method for the Detection of S -Nitrosylated Proteins
Jaffrey, S. R., & Snyder, S. H. (2001) · Science Signaling · doi:10.1126/stke.2001.86.pl1 · Cited by 855
Regulation of protein function by S‐glutathiolation in response to oxidative and nitrosative stress
Klatt, P., & Lamas, S. (2000) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2000.01601.x · Cited by 757
Siddiquee, K., Zhang, S., Guida, W. C., Blaskovich, M. A., Greedy, B. M., Lawrence, H. R., Yip, M. L. R., Jove, R., McLaughlin, M. M., Lawrence, N. J., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0609757104 · Cited by 741
Mechanisms of reversible protein glutathionylation in redox signaling and oxidative stress
Gallogly, M. M., & Mieyal, J. J. (2007) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2007.06.003 · Cited by 476
Reynaert, N. L., van der Vliet, A., Guala, A. S., McGovern, T., Hristova, M., Pantano, C., Heintz, N. H., Heim, J., Ho, Y.-S., Matthews, D. E., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0603290103 · Cited by 442
Shelton, M. D., Chock, P., & Mieyal, J. J. (2005) · Antioxidants and Redox Signaling · doi:10.1089/ars.2005.7.348 · Cited by 425
Pineda‐Molina, E., Klatt, P., Vázquez, J., Marina, A., de Lacoba, M. G., Pérez‐Sala, D., & Lamas, S. (2001) · Biochemistry · doi:10.1021/bi011459o · Cited by 389
Alonzi, T., Maritano, D., Gorgoni, B., Rizzuto, G., Libert, C., & Poli, V. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.5.1621-1632.2001 · Cited by 329
Glutaredoxin Exerts an Antiapoptotic Effect by Regulating the Redox State of Akt*
Murata, H., Ihara, Y., Nakamura, H., Yodoi, J., Sumikawa, K., & Kondo, T. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m310171200 · Cited by 304
Redox regulation of c‐Jun DNA binding by reversible S‐glutathiolation
Klatt, P., Pineda‐Molina, E., de Lacoba, M. G., Padilla, C. A., Martı́nez-Galisteo, E., Bárcena, J. A., & Lamas, S. (1999) · The FASEB Journal · doi:10.1096/fasebj.13.12.1481 · Cited by 284
Carballo, M., Conde, M., El Bekay, R., Martı́n-Nieto, J., Camacho, M. J., Monteseirı́n, J., Conde, J., Bedoya, F. J., & Sobrino, F. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.25.17580 · Cited by 266
Thiol–Disulfide Balance: From the Concept of Oxidative Stress to that of Redox Regulation
Ghezzi, P., Bonetto, V., & Fratelli, M. (2005) · Antioxidants and Redox Signaling · doi:10.1089/ars.2005.7.964 · Cited by 241
Antioxidant/Pro-oxidant Equilibrium Regulates HIF-1α and NF-κB Redox Sensitivity
Haddad, J. J., Olver, R. E., & Land, S. C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000737200 · Cited by 239
Velu, C. S., Niture, S. K., Doneanu, C. E., Pattabiraman, N., & Srivenugopal, K. S. (2007) · Biochemistry · doi:10.1021/bi700425y · Cited by 205
Oxidative stress inhibits MEKK1 by site-specific glutathionylation in the ATP-binding domain
Cross, J. V., & Templeton, D. J. (2004) · Biochemical Journal · doi:10.1042/bj20040591 · Cited by 200
A Novel Role for Human Sulfiredoxin in the Reversal of Glutathionylation
Findlay, V. J., Townsend, D. M., Morris, T. E., Fraser, J. P., He, L., & Tew, K. D. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0484 · Cited by 198
Glutathiolation Regulates Tumor Necrosis Factor-α–Induced Caspase-3 Cleavage and Apoptosis
Pan, S., & Berk, B. C. (2006) · Circulation Research · doi:10.1161/01.res.0000256089.30318.20 · Cited by 169
Fu, A. K. Y., Fu, W., Ng, A. K. Y., Chien, W. W. Y., Ng, Y.-P., Wang, J. H.-C., & Ip, N. Y. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307606100 · Cited by 143
The 20S proteasome processes NF‐κB1 p105 into p50 in a translation‐independent manner
Moorthy, A. K., Savinova, O. V., Ho, J. Q., Wang, V. Y., Vu, D., & Ghosh, G. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601081 · Cited by 140
Li, W.-C., Ye, S., Sun, R., Liu, Y., Tang, Z., Kim, Y., Karras, J. G., & Zhang, H. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-0484 · Cited by 139
Regulation of Mitochondrial NADP+-dependent Isocitrate Dehydrogenase Activity by Glutathionylation
Kil, I. S., & Park, J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411306200 · Cited by 137
Clavreul, N., Adachi, T. K., Pimental, D. R., Ido, Y., Schöneich, C., & Cohen, R. A. (2006) · The FASEB Journal · doi:10.1096/fj.05-4875fje · Cited by 130
Glutaredoxin Regulates Nuclear Factor κ-B and Intercellular Adhesion Molecule in Müller Cells
Shelton, M. D., Kern, T. S., & Mieyal, J. J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610863200 · Cited by 126
Ser727-dependent transcriptional activation by association of p300 with STAT3 upon IL-6 stimulation
Schuringa, J.-J., Schepers, H., Vellenga, E., & Kruijer, W. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)02354-7 · Cited by 124
Role of Protein -SH Groups in Redox Homeostasis— The Erythrocyte as a Model System
Simplicio, P. D., Cacace, M. G., Lusini, L., Giannerini, F., Giustarini, D., & Rossi, R. (1998) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1998.0694 · Cited by 123
Interleukin-6 trans-signaling in inflammatory bowel disease.
Mitsuyama, K., Sata, M., & Rose-John, S. (2006) · Cytokine & growth factor reviews · doi:10.1016/j.cytogfr.2006.09.003 · Cited by 122
Pin1 is required for the Ser727 phosphorylation-dependent Stat3 activity
Lufei, C., Koh, T. H., Uchida, T., & Cao, X. (2007) · Oncogene · doi:10.1038/sj.onc.1210567 · Cited by 106
Oxidation and S-Nitrosylation of Cysteines in Human Cytosolic and Mitochondrial Glutaredoxins
Hashemy, S. I., Johansson, C., Berndt, C., Lillig, C. H., & Holmgren, A. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700927200 · Cited by 103
Ho, Y.-S., Xiong, Y., Ho, D. S., Gao, J., Chua, B. H. L., Pai, H. V., & Mieyal, J. J. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.07.025 · Cited by 101
Formation of disulfides with diamide
Kosower, N. S., & Kosower, E. M. (1987) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(87)43050-4 · Cited by 98
NOV-002, a Glutathione Disulfide Mimetic, as a Modulator of Cellular Redox Balance
Townsend, D. M., He, L., Hutchens, S., Garrett, T. E., Pazoles, C. J., & Tew, K. D. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5957 · Cited by 94
Choudhari, S. R., Khan, M. A., Harris, G., Picker, D., Jacob, G. S., Block, T., & Shailubhai, K. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-06-0561 · Cited by 90
Daily, D., Vlamis‐Gardikas, A., Offen, D., Mittelman, L. A., Melamed, E., Holmgren, A., & Barzilai, A. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101400200 · Cited by 85
Purification and properties of thioltransferase.
Gan, Z., & Wells, W. W. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)36043-x · Cited by 84
Sun, X., Zhang, J., Wang, L., & Tian, Z. (2008) · Cancer Letters · doi:10.1016/j.canlet.2007.12.009 · Cited by 80
Regulation of Annexin A2 by Reversible Glutathionylation
Caplan, J. F., Filipenko, N. R., Fitzpatrick, S. L., & Waisman, D. M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313049200 · Cited by 77
Glutathionylation of beta-actin via a cysteinyl sulfenic acid intermediary
Johansson, M., & Lundberg, M. (2007) · BMC Biochemistry · doi:10.1186/1471-2091-8-26 · Cited by 74
Akt Modulates STAT3-mediated Gene Expression through a FKHR (FOXO1a)-dependent Mechanism
Kortylewski, M., Feld, F., Krüger, K.-D., Bahrenberg, G., Roth, R. A., Joost, H., Heinrich, P. C., Behrmann, I., & Barthel, A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m205403200 · Cited by 73
Mazière, C., Alimardani, G., Dantin, F., Dubois, F., Conte, M.-A., & Mazière, J. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00324-5 · Cited by 73
Wild, A. C., & Mulcahy, R. (1999) · PubMed · Cited by 72
Crif1 is a novel transcriptional coactivator of STAT3
Kwon, M. C., Koo, B., Moon, J.-S., Kim, Y. Y., Park, K. C., Kim, N.-S., Kwon, M. Y., Kong, M.-P., Yoon, K., Im, S.-K., et al. (2008) · The EMBO Journal · doi:10.1038/sj.emboj.7601986 · Cited by 65
Regulation of the CLDN3 gene in ovarian cancer cells
Honda, H., Pazin, M. J., D’Souza, T., Ji, H., & Morin, P. J. (2007) · Cancer Biology & Therapy · doi:10.4161/cbt.6.11.4832 · Cited by 65
Self-citationInhibition of Stat3 activity by YC-1 enhances chemo-sensitivity in hepatocellular carcinoma
Lau, C. K., Yang, Z. F., Lam, S. P., Lam, C. T., Ngai, P., Tam, K. H., Poon, R. T. P., & Fan, S.-T. (2007) · Cancer Biology & Therapy · doi:10.4161/cbt.6.12.4970 · Cited by 62
Wild, A. C., & Mulcahy, R. (1999) · Biochemical Journal · doi:10.1042/0264-6021:3380659 · Cited by 61
Tie-nian, Z., He, H., Kole, S., D’Souza, T., Agarwal, R., Morin, P. J., & Bernier, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611430200 · Cited by 56
Self-citationDemetris, A. J. (2006) · World Journal of Gastroenterology · doi:10.3748/wjg.v12.i22.3512 · Cited by 52
Huang, H. F. S., Murphy, T. F., Shu, P., Barton, A. B., & Barton, B. E. (2005) · Molecular Cancer · doi:10.1186/1476-4598-4-2 · Cited by 52
Bode, J. G., Schweigart, J., Kehrmann, J., Ehlting, C., Schaper, F., Heinrich, P. C., & Häussinger, D. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.1.257 · Cited by 48
Human papillomavirus infection and invasive cervical neoplasia: a study of prevalence and morphology
Zehbe, I., & Wilander, E. (1997) · The Journal of Pathology · doi:10.1002/(sici)1096-9896(199703)181:3 · Cited by 41
CRAGHILL, J., Cronshaw, A. D., & Harding, J. J. (2004) · Biochemical Journal · doi:10.1042/bj20031367 · Cited by 40
Glutathionylation of Two Cysteine Residues in Paired Domain Regulates DNABinding Activity ofPax-8
Cao, X., Kambe, F., Lu, X., Kobayashi, N., Ohmori, S., & Seo, H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411443200 · Cited by 40
He, H., Zhu, T. N., Xie, Y., Fan, J., Kole, S., Saxena, S. P., & Bernier, M. (2006) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)84049-8 · Cited by 39
Self-citationDemetris, , J., Lunz, Susan, S., Specht, Isao, I., & Nozaki (2006) · Cited by 36
Wang, Y., Xie, Y., Bernier, M., & Wainer, I. W. (2008) · Journal of Chromatography A · doi:10.1016/j.chroma.2008.06.027 · Cited by 24
Self-citationP53 status influences regulation of HSPs and ribosomal proteins by PDTC and radiation
THOMPSON, J. S., Asmis, R., Glass, J., Liu, H., Wilson, C., Nelson, B., Brown, S. A., & Stromberg, A. J. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.02.159 · Cited by 9
Tacchini, L., Fusar-Poli, D., Sironi, M., Mantovani, A., & Bernelli‐Zazzera, A. (2003) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(02)00164-4 · Cited by 7
Flagged first, then by citations
1 of the 61 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Signaling Functions of Reactive Oxygen Species
Forman, H. J., Maiorino, M., & Ursini, F. (2010) · Biochemistry · doi:10.1021/bi9020378 · Cited by 827
Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314
“The transactivation domain (TAD) plays a role in the recruitment of coactivators with histone acetyltransferase activity to facilitate transcriptional activation.”
BackgroundInfluentialSTAT proteins in cancer: orchestration of metabolism
Li, Y., Zhang, C., Martincuks, A., Herrmann, A., & Yu, H. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-022-00537-3 · Cited by 305
Glutathione S-Transferases in Cancer
Singh, R. R., & Reindl, K. M. (2021) · Antioxidants · doi:10.3390/antiox10050701 · Cited by 245
Protein Oxidative Modifications: Beneficial Roles in Disease and Health.
Cai, Z., & Yan, L. (2013) · PubMed · Cited by 227
Metadata
- Authors
- Xie, Y., Kole, S., Precht, P., Pazin, M. J., & Bernier, M.
- Affiliations
- National Institutes of Health (US)
- MedStar Health Research Institute (US)
- Corresponding author
- Bernier, Michel
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2008-11-06
- Volume
- 150
- Issue
- 3
- Pages
- 1122-1131
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC2654735
- OpenAlex
- W1996740511
- Cited by
- 126
- References
- 61
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 9 · 2020: 10 · 2019: 8 · 2018: 4 · 2017: 11 · 2016: 7 · 2015: 9 · 2014: 13 · 2013: 12 · 2012: 5
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (ZIAAG000378)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- S-glutathionylation, STAT3, cysteine oxidation, glutaredoxin 1, IL-6 signaling, STAT3 tyrosine phosphorylation, nuclear translocation, DNA-binding activity, oxidative stress, diamide, pyrrolidine dithiocarbamate, protein thiol modification
- MeSH terms
- Antioxidants, Cells, Cultured, Cysteine, Diamines, Glutathione, Humans, Phosphorylation, Protein Processing, Post-Translational, Pyrrolidines, Thiocarbamates, Transfection, Signal Transduction, Interleukin-6, Oxidants, STAT3 Transcription Factor, Janus Kinase 2, Glutaredoxins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
