Cellular Redox Imbalance and Changes of Protein S-glutathionylation Patterns Are Associated with Senescence Induced by Oncogenic H-Ras
Open accessAbstract
H-Ras oncogene requires deregulation of additional oncogenes or inactivation of tumor suppressor proteins to increase cell proliferation rate and transform cells. In fact, the expression of the constitutively activated H-RasV12 induces cell growth arrest and premature senescence, which act like barriers in pre-neoplastic lesions. In our experimental model, human fibroblasts transfected with H-RasV12 show a dramatic modification of morphology. H-RasV12 expressing cells also show premature senescence followed by cell death, induced by autophagy and apoptosis. In this context, we provide evidence that in H-RasV12 expressing cells, the premature senescence is associated with cellular redox imbalance as well as with altered post-translation protein modification. In particular, redox imbalance is due to a strong reduction of total antioxidant capacity, and significant decrease of glutathione level. As the reversible addition of glutathione to cysteinyl residues of proteins is an important post-translational regulative modification, we investigated S-glutathionylation in cells expressing active H-Ras. In this contest we observed different S-glutathionylation patterns in control and H-RasV12 expressing cells. Particularly, the GAPDH enzyme showed S-glutathionylation increase and significant enzyme activity depletion in H-Ras V12 cells. In conclusion, we proposed that antioxidant defense reduction, glutathione depletion and subsequent modification of S-glutathionylation of target proteins contribute to arrest cell growth, leading to death of fibroblasts expressing constitutively active H-Ras oncogene, thus acting as oncogenic barriers that obstacle the progression of cell transformation.
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
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?
Normal aging and cellular senescence are conditions influenced by oxidative stress.
“both conditions influenced by OS [183,184,185,186].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [184]
A reduction in GSH and the GSH/GSSG ratio is often reported during normal aging and in cellular senescence.
“a reduction in GSH and the GSH/GSSG ratio are often reported during normal aging and in cellular senescence, both conditions influenced by OS [183,184,185,186].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [184]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Bradford, M. M. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90527-3 · Cited by 255,302 · see citing works
Hanahan, D., & Weinberg, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)81683-9 · Cited by 29,219 · see citing works
Free radicals, metals and antioxidants in oxidative stress-induced cancer
Valko, M., Rhodes, C. J., Moncol, J., Izakovic, M., & Mazur, M. (2006) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2005.12.009 · Cited by 6,680 · see citing works
Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes
Land, H., Parada, L. F., & Weinberg, R. A. (1983) · Nature · doi:10.1038/304596a0 · Cited by 2,804 · see citing works
Purification and characterization of the flavoenzyme glutathione reductase from rat liver.
Carlberg, I., & Mannervik, B. (1975) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)41206-4 · Cited by 2,024 · see citing works
Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints
Bartkova, J., Rezaei, N., Liontos, M., Karakaidos, P., Kletsas, D., Issaeva, N., Vassiliou, L.-V. F., Kolettas, E., Niforou, K., Zoumpourlis, V. C., et al. (2006) · Nature · doi:10.1038/nature05268 · Cited by 1,986 · see citing works
Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication
Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., Schurra, C., Garre’, M., Giovanni Nuciforo, P., Bensimon, A., et al. (2006) · Nature · doi:10.1038/nature05327 · Cited by 1,821 · see citing works
Principles of cancer therapy: oncogene and non-oncogene addiction
Luo, J., Solimini, N. L., & Elledge, S. J. (2009) · Cell · doi:10.1016/j.cell.2009.02.024 · Cited by 1,765 · see citing works
Glutathione dysregulation and the etiology and progression of human diseases
Ballatori, N., Krance, S. M., Notenboom, S., Shi, S., Tieu, K., & Hammond, C. L. (2009) · Biological Chemistry · doi:10.1515/bc.2009.033 · Cited by 1,118 · see citing works
Glutathione in Cancer Biology and Therapy
Estrela, J. M., Ortega, A., & Obrador, E. (2006) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408360500523878 · Cited by 1,041 · see citing works
The role of glutathione in cancer
Balendiran, G. K., Dabur, R., & Fraser, D. A. (2004) · Cell Biochemistry and Function · doi:10.1002/cbf.1149 · Cited by 929 · see citing works
Novel functions of vimentin in cell adhesion, migration, and signaling
Ivaska, J., Pallari, H., Nevo, J., & Eriksson, J. (2007) · Experimental Cell Research · doi:10.1016/j.yexcr.2007.03.040 · Cited by 786 · see citing works
DNA damage checkpoints: from initiation to recovery or adaptation
Bartek, J., & Lukas, J. (2007) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2007.02.009 · Cited by 784 · see citing works
Hellman, U., Wernstedt, C., Góñez, L. J., & Heldin, C. (1995) · Analytical Biochemistry · doi:10.1006/abio.1995.1070 · Cited by 753 · see citing works
Ras Proteins Induce Senescence by Altering the Intracellular Levels of Reactive Oxygen Species
Lee, A. C., Fenster, B. E., Ito, H., Takeda, K., Bae, N. S., Hirai, T., Yu, Z.-X., Ferrans, V. J., Howard, B. H., & Finkel, T. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.12.7936 · Cited by 691 · see citing works
Redox modifications of protein-thiols: emerging roles in cell signaling.
Biswas, S., Chida, A., & Rahman, I. (2006) · Biochemical Pharmacology · doi:10.1016/j.bcp.2005.10.044 · Cited by 631 · see citing works
Fratelli, M., Demol, H., Puype, M., Casagrande, S., Eberini, I., Salmona, M., Bonetto, V., Mengozzi, M., Duffieux, F., Miclet, E., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.052592699 · Cited by 556 · see citing works
The Identity of Glutathione S -Transferase B with Ligandin, a Major Binding Protein of Liver
Habig, W. H., Pabst, M. J., Fleischner, G., et al. (1974) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.71.10.3879 · Cited by 539 · see citing works
Molecular Mechanisms and Clinical Implications of Reversible Protein <i>S</i> -Glutathionylation
Mieyal, J. J., Gallogly, M. M., Qanungo, S., Sabens, E. A., & Shelton, M. D. (2008) · Antioxidants & Redox Signaling · doi:10.1089/ars.2008.2089 · Cited by 523 · see citing works
Methods to Detect Biomarkers of Cellular Senescence
Itahana, K., Campisi, J., & Dimri, G. P. (2007) · Methods in molecular biology · doi:10.1007/978-1-59745-361-5_3 · Cited by 516 · see citing works
Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis
Sarkisian, C. J., Keister, B. A., Stairs, D. B., Boxer, R. B., Moody, S. E., & Chodosh, L. A. (2007) · Nature Cell Biology · doi:10.1038/ncb1567 · Cited by 490 · see citing works
Elgendy, M., Sheridan, C., Brumatti, G., & Martin, S. J. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.02.009 · Cited by 426 · see citing works
Regoli, F., & Winston, G. W. (1999) · Toxicology and Applied Pharmacology · doi:10.1006/taap.1999.8637 · Cited by 402 · see citing works
The Neglected Intrinsic Resistome of Bacterial Pathogens
Fajardo-Lubian, A., Martinez-Martín, N., Mercadillo, M., Galán, J. C., Ghysels, B., Matthijs, S., Cornélis, P., Wiehlmann, L., Tümmler, B., Baquero, F., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001619 · Cited by 368 · see citing works
The cell cycle is a redox cycle: Linking phase-specific targets to cell fate
Burhans, W. C., & Heintz, N. H. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.05.026 · Cited by 359 · see citing works
Brigelius, R., Muckel, C., Akerboom, T. P. M., & Sies, H. (1983) · Biochemical Pharmacology · doi:10.1016/0006-2952(83)90014-x · Cited by 348 · see citing works
Ralph, S. J., Rodríguez‐Enríquez, S., Neužil, J., Saavedra, E., & Moreno‐Sánchez, R. (2010) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2010.02.008 · Cited by 335 · see citing works
S-Glutathionylation: From Molecular Mechanisms to Health Outcomes
Xiong, Y., Uys, J. D., Tew, K. D., & Townsend, D. M. (2011) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3540 · Cited by 314 · see citing works
Mohr, S., Hallak, H., de Boitte, A., Lapetina, E. G., & Brüne, B. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.14.9427 · Cited by 309 · see citing works
Adachi, T. K., Pimentel, D. R., Heibeck, T. H., Hou, X., Lee, Y. J., Jiang, B., Ido, Y., & Cohen, R. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313320200 · Cited by 301 · see citing works
Molecular Mechanisms and Potential Clinical Significance of S -Glutathionylation
Dalle‐Donne, I., Milzani, A., Gagliano, N., Colombo, R., Giustarini, D., & Rossi, R. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1716 · Cited by 296 · see citing works
Oncogenic <i>ras</i> and p53 Cooperate To Induce Cellular Senescence
Ferbeyre, G., de Stanchina, E., Lin, A. W., Querido, E., McCurrach, M. E., Hannon, G. J., & Lowe, S. W. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.10.3497-3508.2002 · Cited by 290 · see citing works
S‐Glutathionylation: from redox regulation of protein functions to human diseases
Giustarini, D., Rossi, R., Milzani, A., Colombo, R., & Dalle‐Donne, I. (2004) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2004.tb00275.x · Cited by 279 · see citing works
Duan, J., Duan, J., Zhang, Z., & Tong, T. (2005) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2005.01.010 · Cited by 229 · see citing works
Martı́nez-Ruiz, A., & Lamas, S. (2007) · Cardiovascular Research · doi:10.1016/j.cardiores.2007.03.016 · Cited by 197 · see citing works
The Redox Regulation of Thiol Dependent Signaling Pathways in Cancer
Giles, G. I. (2006) · Current Pharmaceutical Design · doi:10.2174/138161206779010549 · Cited by 182 · see citing works
Garcia, J., Han, D., Sancheti, H., Yap, L.-P., Kaplowitz, N., & Cadenas, E. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.164160 · Cited by 178 · see citing works
Bártková, J., Hamerlik, P., Stockhausen, M.-T., Ehrmann, J., Hlobílková, A., Laursen, H. B., Kalita, O., Kolář, Z., Poulsen, H. S., Broholm, H., et al. (2010) · Oncogene · doi:10.1038/onc.2010.249 · Cited by 170 · see citing works
Hole, P. S., Pearn, L., Tonks, A. J., James, P. E., Burnett, A. K., Darley, R. L., & Tonks, A. (2009) · Blood · doi:10.1182/blood-2009-06-222869 · Cited by 138 · see citing works
Tu, S., Chang, C.-C., Chen, C.-S., Tam, K., Wang, Y., Lee, C., Lin, H. W., Cheng, T., Huang, C.-S., Chu, J., et al. (2009) · Breast Cancer Research and Treatment · doi:10.1007/s10549-009-0492-0 · Cited by 134 · see citing works
Marzia Perluigi, A., Domenico, F. D., Giorgi, A., Schininà, M. E., Coccia, R., Cini, C., Bellia, F., Cambria, M. T., Cornelius, C., Butterfield, D. A., et al. (2010) · Journal of Neuroscience Research · doi:10.1002/jnr.22500 · Cited by 109 · see citing works
Nicke, B., Bastien, J., Khanna, S. J., Warne, P. H., Cowling, V., Cook, S. J., Peters, G., Delpuech, O., Schulze, A., Berns, K., et al. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.10.038 · Cited by 108 · see citing works
Townsend, D. M., Findlay, V. J., Fazilev, F., Ogle, M. E., Fraser, J. P., Saavedra, J. E., Ji, X., Keefer, L. K., & Tew, K. D. (2005) · Molecular Pharmacology · doi:10.1124/mol.105.018523 · Cited by 105 · see citing works
Improvement of N-glycan site occupancy of therapeutic glycoproteins produced in Pichia pastoris
Choi, B., Warburton, S., Lin, H., Patel, R., Boldogh, I. R., Meehl, M., d′Anjou, M., Pon, L. A., Stadheim, T. A., & Sethuraman, N. (2012) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-012-4067-3 · Cited by 101 · see citing works
Vayalil, P. K., Iles, K. E., Choi, J., Yi, A., Postlethwait, E. M., & Liu, R.-M. (2007) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00128.2007 · Cited by 92 · see citing works
Glutathione Regulates Telomerase Activity in 3T3 Fibroblasts
Borrás, C., Esteve, J. M., Vinã, J. R., Sastre, J., Viña, J., & Pallardó, F. V. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402425200 · Cited by 84 · see citing works
The Senescent Side of Tumor Suppression
Collado, M., & Serrano, M. (2005) · Cell Cycle · doi:10.4161/cc.4.12.2260 · Cited by 79 · see citing works
Thamsen, M., & Jakob, U. (2010) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2010.11.013 · Cited by 77 · see citing works
Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species
Lee, J. J., Lee, J. H., Ko, Y. G., Hong, S., & Js, L. (2009) · Oncogene · doi:10.1038/onc.2009.355 · Cited by 66 · see citing works
Banerjee, P., Basu, A., Datta, D. B., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.248401 · Cited by 62 · see citing works
Role of glutathione in cell nucleus
Marković, J., García‐Giménez, J. L., Gimeno, A., et al. (2010) · Free Radical Research · doi:10.3109/10715762.2010.485989 · Cited by 61 · see citing works
Glutathionylation pathways in drug response
Ghezzi, P., & Simplicio, P. D. (2007) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2007.04.006 · Cited by 54 · see citing works
Redox platforms in cancer drug discovery and development
Tew, K. D., & Townsend, D. M. (2010) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2010.10.016 · Cited by 54 · see citing works
Quantitative digital in situ senescence-associated β-galactosidase assay
Shlush, L. I., Itzkovitz, S., Cohen, A. A., Rutenberg, A., Berkovitz, R., Yehezkel, S., Shahar, H., Selig, S., & Skorecki, K. L. (2011) · BMC Cell Biology · doi:10.1186/1471-2121-12-16 · Cited by 49 · see citing works
Serù, R., Mondola, P., Damiano, S., Svegliati, S., Agnese, S., Avvedimento, E. V., & Santillo, M. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02754.x · Cited by 46 · see citing works
Yusuf, M., Chuang, T. L., Bhat, G., & Srivenugopal, K. (2010) · Free Radical Biology & Medicine · doi:10.1016/j.freeradbiomed.2010.06.020 · Cited by 45 · see citing works
Liu, R., Li, B., & Qiu, M. S. (2001) · Oncogene · doi:10.1038/sj.onc.1204214 · Cited by 43 · see citing works
Gilge, J. L., Fisher, M. J., & Chai, Y.-C. (2008) · PLoS ONE · doi:10.1371/journal.pone.0004015 · Cited by 35 · see citing works
Magherini, F., Carpentieri, A., Amoresano, A., Gamberi, T., Filippo, C. D., Rizzetto, L., Biagini, M., Pucci, P., & Modesti, A. (2009) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-009-8574-z · Cited by 34 · see citing works
Self-citationGenes of Human ATP Synthase: Their Roles in Physiology and Aging
Kagawa, Y., Hamamoto, T., Endo, H., et al. (1997) · Bioscience Reports · doi:10.1023/a:1027329328504 · Cited by 24 · see citing works
Andrei, D., Maciag, A. E., Chakrapani, H., Citro, M. L., Keefer, L. K., & Saavedra, J. E. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm800831y · Cited by 21 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence
Varesi, A., Chirumbolo, S., Campagnoli, L. I. M., Pierella, E., Piccini, G. B., Carrara, A., Ricevuti, G., Scassellati, C., Bonvicini, C., & Pascale, A. (2022) · Antioxidants · doi:10.3390/antiox11071224 · Cited by 145 · see citing works
MicroRNAs, Long Non-Coding RNAs, and Circular RNAs in the Redox Control of Cell Senescence
Lettieri-Barbato, D., Aquilano, K., Punziano, C., Minopoli, G., & Faraonio, R. (2022) · Antioxidants · doi:10.3390/antiox11030480 · Cited by 51 · see citing works
- Authors
- Armeni, T., Ercolani, L., Urbanelli, L., Magini, A., Magherini, F., Pugnaloni, A., Piva, F., Modesti, A., Emiliani, C., & Principato, G.
- Affiliations
- Marche Polytechnic University (IT)
- University of Perugia (IT)
- University of Florence (IT)
- Corresponding author
- Armeni, Tatiana
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-12-20
- Volume
- 7
- Issue
- 12
- Pages
- e52151
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3527427
- OpenAlex
- W2040358545
- Cited by
- 28
- References
- 61
- Citations by year
- 2025: 1 · 2023: 2 · 2022: 4 · 2021: 1 · 2020: 5 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 1 · 2015: 2 · 2014: 2 · 2013: 2
- FWCI
- 0.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
- Funders
- Fondazione Cassa di Risparmio di Perugia (2008.021.375)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- H-Ras V12, premature senescence, S-glutathionylation, glutathione depletion, antioxidant capacity, post-translational modification, glyceraldehyde-3-phosphate dehydrogenase, human fibroblasts, autophagy, apoptosis, cell transformation
- MeSH terms
- Antioxidants, Autophagy, Cell Cycle, Cell Line, Humans, Oxidation-Reduction, Genes, ras, Mass Spectrometry, Immunoblotting, Electrophoresis, Gel, Two-Dimensional, Cellular Senescence, Cell Death, Apoptosis, Reactive Oxygen Species
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
