Pro- and anti-apoptotic roles of c-Jun N-terminal kinase (JNK) in ethanol and acetaldehyde exposed rat hepatocytes
Abstract
We have examined the significance of the activation of c-Jun N-terminal kinase (JNK) and p42/44 mitogen-activated protein kinase (MAPK) by ethanol and acetaldehyde in rat hepatocyte apoptosis. Acetaldehyde induced rapid and transient (15 min) activation of p42/44 MAPK followed by activation of JNK, which remained above control up to 1 h. Ethanol activated JNK for up to 4 h. Both ethanol and acetaldehyde caused apoptosis as determined by DNA fragmentation, caspase-3 activation and 2'[4-ethoxyphenyl]-5-[4-methyl-piperazinyl]-2,5'-bi-1H-benzimidazole (Hoechst 33342) staining. Ethanol-induced apoptosis was blocked by JNK inhibitor 1,9-pyrazoloanthrone (SP600125), indicating that JNK activation is pro-apoptotic. In contrast, acetaldehyde-induced apoptosis was not suppressed by this inhibitor. In fact, SP600125 potentiated acetaldehyde-induced apoptosis, suggesting that JNK activation is anti-apoptotic. Inhibition of p42/44 MAPK by MAPK kinase (MKK1) inhibitor, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126), potentiated apoptosis by acetaldehyde or ethanol, suggesting anti-apoptotic role of p42/44 MAPK. The activation of JNK by ethanol or acetaldehyde was insensitive to the genistein (tyrosine kinase inhibitor), GF109203X (2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide, protein kinase C [PKC] inhibitor) and N-acetylcysteine (N-AC) (antioxidant), whereas p42/44 MAPK activation by acetaldehyde was inhibited by genistein and GF109203X. Furthermore, p42/44 MAPK activation is not necessary for the JNK activation. In summary, transient activation of JNK by acetaldehyde is anti-apoptotic, whereas sustained activation of JNK by ethanol is pro-apoptotic. The activation of p42/44 MAPK appears to be anti-apoptotic for both ethanol and acetaldehyde. Thus, JNK activation by ethanol and acetaldehyde can be both pro- and anti-apoptotic in hepatocytes.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Acute exposure to many hepatotoxic agents including alcohol, APAP, arachidonic acid, 4-HNE and carbon tetrachloride, palmitic acid, and troglitazone significantly activated JNK and/or p38K, contributing to toxicity in a variety of cells.
“In fact, acute exposure to many hepatotoxic agents including alcohol [110], [111], APAP [112], [113], [114], [115], [116], arachidonic acid [117], 4-HNE and carbon tetrachloride [118], palmitic acid [119], and troglitazone [120] significantly activated JNK (p-JNK) and/or p38K (p-p38K), contributing to toxicity in a variety of cells.”
Cites
Mammalian MAP kinase signalling cascades
Chang, L., & Karin, M. (2001) · Nature · doi:10.1038/35065000 · Cited by 5,118 · see citing works
Hibi, M., Lin, A., Smeal, T., Minden, A., & Karin, M. (1993) · Genes & Development · doi:10.1101/gad.7.11.2135 · Cited by 1,886 · see citing works
Bass, D., Parce, J. W., DeChatelet, L. R., Szejda, P., Seeds, M. C., & Thomas, M. (1983) · The Journal of Immunology · doi:10.4049/jimmunol.130.4.1910 · Cited by 1,811 · see citing works
Specificity and mechanism of action of some commonly used protein kinase inhibitors
Davies, S., Reddy, H., Caivano, M., & Cohen, P. (2000) · Biochemical Journal · doi:10.1042/0264-6021:3510095 · Cited by 1,618 · see citing works
The Role of c-Jun N-terminal Kinase (JNK) in Apoptosis Induced by Ultraviolet C and γ Radiation
Chen, Y.-R., Wang, X., Templeton, D., Davis, R. J., & Tan, T.-H. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.50.31929 · Cited by 867 · see citing works
Detection of picomole levels of hydroperoxides using a fluorescent dichlorofluorescein assay
Cathcart, R., Schwiers, E., & Ames, B. N. (1983) · Analytical Biochemistry · doi:10.1016/0003-2697(83)90270-1 · Cited by 857 · see citing works
Protein phosphatases and the regulation of mitogen-activated protein kinase signalling
Keyse, S. M. (2000) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(99)00075-7 · Cited by 808 · see citing works
Oxford textbook of clinical hepatology
Bircher, J. (2000) · Digestive and Liver Disease · doi:10.1016/s1590-8658(00)80409-0 · Cited by 699 · see citing works
Intracellular Signaling by Reactive Oxygen Species during Hypoxia in Cardiomyocytes
Duranteau, J., Chandel, N. S., Kulisz, A., Shao, Z., & Schumacker, P. T. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.19.11619 · Cited by 679 · see citing works
Hepatology. A Textbook of Liver Disease
(1990) · Annals of Internal Medicine · doi:10.7326/0003-4819-113-3-259_2 · Cited by 624 · see citing works
Ethanol, oxidative stress, and cytokine-induced liver cell injury
Hoek, J. B., & Pastorino, J. G. (2002) · Alcohol · doi:10.1016/s0741-8329(02)00215-x · Cited by 478 · see citing works
Hoek, T. L. V., Li, C., Shao, Z., Schumacker, P. T., & Becker, L. B. (1997) · Journal of Molecular and Cellular Cardiology · doi:10.1006/jmcc.1997.0497 · Cited by 398 · see citing works
Hepatology: A Textbook of Liver Disease
O'Grady, J. (1997) · Gut · doi:10.1136/gut.40.4.562 · Cited by 391 · see citing works
Oxford Textbook of Clinical Hepatology
Iber, F. L. (1992) · JAMA · doi:10.1001/jama.1992.03490150162046 · Cited by 364 · see citing works
Brondello, J., Brunet, A., Pouysségur, J., & McKenzie, F. R. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.2.1368 · Cited by 361 · see citing works
Rauen, U., Polzar, B., Stephan, H., Mannherz, H. G., & de GROOT, H. (1999) · The FASEB Journal · doi:10.1096/fasebj.13.1.155 · Cited by 331 · see citing works
DeSilva, D. R., Jones, E. A., Favata, M. F., JAFFEE, B. D., Magolda, R. L., Trzăskos, J. M., & Scherle, P. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.9.4175 · Cited by 295 · see citing works
Ho, F. M., Liu, S., Liau, C. S., Huang, P. J., & Lin‐Shiau, S. Y. (2000) · Circulation · doi:10.1161/01.cir.101.22.2618 · Cited by 288 · see citing works
Hepatocyte apoptosis is a pathologic feature of human alcoholic hepatitis
Natori, S., Rust, C., Stadheim, L. M., Srinivasan, A. N., Burgart, L. J., & Gores, G. J. (2001) · Journal of Hepatology · doi:10.1016/s0168-8278(00)00089-1 · Cited by 268 · see citing works
Src and Cas Mediate JNK Activation but Not ERK1/2 and p38 Kinases by Reactive Oxygen Species
Yoshizumi, M., Abe, J., Haendeler, J., Huang, Q., & Berk, B. C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.16.11706 · Cited by 263 · see citing works
C–Jun–N–Terminal Kinase Drives Cyclin D1 Expression and Proliferation During Liver Regeneration
Schwabe, R. F., Bradham, C. A., Uehara, T., Hatano, E., Bennett, B. L., Schoonhoven, R., & Brenner, D. A. (2003) · Hepatology · doi:10.1053/jhep.2003.50135 · Cited by 251 · see citing works
Dai, Y., Rashba-Step, J., & Cederbaum, A. I. (1993) · Biochemistry · doi:10.1021/bi00078a017 · Cited by 240 · see citing works
Meriin, A. B., Yaglom, J. A., Gabai, V. L., Mosser, D. D., Zon, L. I., & Sherman, M. Y. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.4.2547 · Cited by 237 · see citing works
N-Acetylcysteine and glutathione as inhibitors of tumor necrosis factor production
Peristeris, P., Clark, B. D., Gatti, S., Faggioni, R., Mantovani, A., Mengozzi, M., Orencole, S. F., Sironi, M., & Ghezzi, P. (1992) · Cellular Immunology · doi:10.1016/0008-8749(92)90205-4 · Cited by 236 · see citing works
Surapisitchat, J., Hoefen, R. J., Pi, X., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.101134098 · Cited by 229 · see citing works
Inhibition of PTPs by H2O2 regulates the activation of distinct MAPK pathways
Lee, K., & Esselman, W. J. (2002) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(02)01000-6 · Cited by 218 · see citing works
MAP kinase signaling in diverse effects of ethanol
Aroor, A. R., & Shukla, S. D. (2004) · Life Sciences · doi:10.1016/j.lfs.2003.11.001 · Cited by 204 · see citing works
Self-citationA Critical Involvement of Oxidative Stress in Acute Alcohol-Induced Hepatic TNF-α Production
Zhou, Z., Wang, L., Song, Z., Lambert, J. C., McClain, C. J., & Kang, Y. J. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63473-6 · Cited by 203 · see citing works
Bubendorf, L., Sauter, G., Moch, H., Schmid, H., Gasser, T. C., Jordan, P., & Mihatsch, M. J. (1996) · The Journal of Pathology · doi:10.1002/(sici)1096-9896(199604)178:4 · Cited by 201 · see citing works
Liu, H., Lo, C. R., & Czaja, M. J. (2002) · Hepatology · doi:10.1053/jhep.2002.32534 · Cited by 199 · see citing works
Cross-talk between JNK/SAPK and ERK/MAPK Pathways
Shen, Y. H., Godlewski, J., Zhu, J., Sathyanarayana, P., Leaner, V., Birrer, M. J., Rana, A., & Tzivion, G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303264200 · Cited by 190 · see citing works
Tombes, R. M., AUER, L. K., Mikkelsen, R. B., Valerie, K. C., Wymann, M. P., MARSHALL, J. C., McMahon, M., & Dent, P. (1998) · Biochemical Journal · doi:10.1042/bj3301451 · Cited by 182 · see citing works
Nlemelä, O., Parkkila, S., Ylä‐Herttuala, S., Villanueva, J. A., Ruebner, B. H., & Halsted, C. H. (1995) · Hepatology · doi:10.1002/hep.1840220428 · Cited by 172 · see citing works
Mechanisms of antiapoptotic effects of estrogens in nigral dopaminergic neurons
Sawada, H., Ibi, M., Kihara, T., Urushitani, M., Honda, K., Nakanishi, M., Akaike, A., & Shimohama, S. (2000) · The FASEB Journal · doi:10.1096/fasebj.14.9.1202 · Cited by 154 · see citing works
Role of ischemia in causing apoptosis, atrophy, and nodular hyperplasia in human liver
Shimamatsu, K., & Wanless, I. R. (1997) · Hepatology · doi:10.1002/hep.510260214 · Cited by 149 · see citing works
NIEMELA, O. (1995) · Hepatology · doi:10.1016/0270-9139(95)90630-4 · Cited by 149 · see citing works
Matsumaru, K., Ji, C., & Kaplowitz, N. (2003) · Hepatology · doi:10.1053/jhep.2003.50230 · Cited by 143 · see citing works
Hirsch, D. D., & Stork, P. J. S. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.7.4568 · Cited by 127 · see citing works
Auer, K. L., Contessa, J. N., Verca, S. B., Pirola, L., Rusconi, S., Cooper, G. M., Abo, A., Wymann, M. P., Davis, R. J., Birrer, M. J., et al. (1998) · Molecular Biology of the Cell · doi:10.1091/mbc.9.3.561 · Cited by 127 · see citing works
Webster, C. R. L., & Anwer, S. M. (1998) · Hepatology · doi:10.1002/hep.510270519 · Cited by 118 · see citing works
III. JNK/AP-1 regulation of hepatocyte death
Czaja, M. J. (2003) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00549.2002 · Cited by 117 · see citing works
Jianping, C. H. E. N., Ishac, E. J. N., Dent, P., Kunos, G., & Gao, B. (1998) · Biochemical Journal · doi:10.1042/bj3340669 · Cited by 107 · see citing works
Graf, D., Kurz, A. K., Fischer, R., Reinehr, R., & Häussinger, D. (2002) · Gastroenterology · doi:10.1053/gast.2002.32976 · Cited by 97 · see citing works
Nuutinen, H. U., Salaspuro, M. P., Valle, M., & Lindros, K. O. (1984) · European Journal of Clinical Investigation · doi:10.1111/j.1365-2362.1984.tb01186.x · Cited by 96 · see citing works
Ikeyama, S., Kusumoto, K., Miyake, H., et al. (2001) · Journal of Hepatology · doi:10.1016/s0168-8278(01)00053-8 · Cited by 91 · see citing works
Liu, H., Jones, B., Bradham, C. A., & Czaja, M. J. (2002) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00304.2001 · Cited by 87 · see citing works
Román, J., Colell, A., Blasco, C., Caballería, J., Parés, A. R., Rodés, J., & Fernández-Checa, J. C. (1999) · Hepatology · doi:10.1002/hep.510300623 · Cited by 86 · see citing works
Hepatic and other medical disorders of alcoholism: from pathogenesis to treatment.
Lieber, C. S. (1998) · Journal of Studies on Alcohol · doi:10.15288/jsa.1998.59.9 · Cited by 80 · see citing works
Wei, S., Rothstein, E. C., Fliegel, L., Dell’Italia, L. J., & Lucchesi, P. A. (2001) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.2001.281.5.c1542 · Cited by 74 · see citing works
Jun kinase modulates tumor necrosis factor-dependent apoptosis in liver cells
Liedtke, C., Plümpe, J., Kubicka, S., Bradham, C. A., Manns, M. P., Brenner, D. A., & Trautwein, C. (2002) · Hepatology · doi:10.1053/jhep.2002.34615 · Cited by 70 · see citing works
Paumelle, R., Tulasne, D., Leroy, C., Coll, J., Vandenbunder, B., & Fafeur, V. (2000) · Molecular Biology of the Cell · doi:10.1091/mbc.11.11.3751 · Cited by 67 · see citing works
Crénesse, D., Gugenheim, J., Hornoy, J., Tornieri, K., Laurens, M., Cambien, B., Le'Negrate, G., Cursio, R., Souza, G. D., Auberger, P., et al. (2000) · Hepatology · doi:10.1053/jhep.2000.19065 · Cited by 66 · see citing works
Retinoic acid inhibits hepatic Jun N-terminal kinase-dependent signaling pathway in ethanol-fed rats
Chung, J., Chavez, P. R. G., Russell, R. M., & Wang, X. (2002) · Oncogene · doi:10.1038/sj.onc.1205023 · Cited by 59 · see citing works
Carter, E. A., & Wands, J. R. (1988) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.1988.tb00241.x · Cited by 51 · see citing works
Role of acetaldehyde in the pathogenesis of alcoholic liver disease
Peters, T. J., & Ward, R. J. (1988) · Molecular Aspects of Medicine · doi:10.1016/0098-2997(88)90022-2 · Cited by 50 · see citing works
Lee, Y. J., Aroor, A. R., & Shukla, S. D. (2002) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.301.3.908 · Cited by 50 · see citing works
Self-citationAcetaldehyde cytotoxicity in cultured rat astrocytes
Hołownia, A., Ledig, M., Braszko, J. J., & Menez, J. F. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01529-2 · Cited by 45 · see citing works
Cardin, R. (2002) · Alcohol and Alcoholism · doi:10.1093/alcalc/37.1.43 · Cited by 45 · see citing works
In vivo modulation of total and mitochondrial glutathione in rat liver
Traber, J., Suter, M., Walter, P. B., & Richter, C. (1992) · Biochemical Pharmacology · doi:10.1016/0006-2952(92)90599-e · Cited by 42 · see citing works
Potentiation of mitogen-activated protein kinase by ethanol in embryonic liver cells
Reddy, M. A., & Shukla, S. D. (1996) · Biochemical Pharmacology · doi:10.1016/s0006-2952(95)02239-2 · Cited by 42 · see citing works
Self-citationZimmerman, B. T., Crawford, G. D., Dahl, R., Simon, F. R., & Mapoles, J. E. (1995) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.1995.tb01527.x · Cited by 40 · see citing works
Weng, Y., & Shukla, S. D. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00313-7 · Cited by 37 · see citing works
Self-citationKoivisto, T., & Salaspuro, M. P. (1997) · PubMed · Cited by 31 · see citing works
Chen, J., Clemens, D. L., Cederbaum, A. I., & Gao, B. (2001) · Clinical Biochemistry · doi:10.1016/s0009-9120(01)00216-8 · Cited by 30 · see citing works
Koivisto, T., & Salaspuro, M. P. (1997) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.1997.tb04495.x · Cited by 29 · see citing works
A perspective on acetaldehyde concentrations and toxicity in man and animals
Brecher, A. S., Hellman, K., & Basista, M. H. (1997) · Alcohol · doi:10.1016/s0741-8329(96)00217-0 · Cited by 27 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Song, B.-J., Akbar, M., Abdelmegeed, M. A., Byun, K., Lee, B., Yoon, S. K., & Hardwick, J. P. (2014) · Redox Biology · doi:10.1016/j.redox.2014.10.004 · Cited by 123 · see citing works
“In fact, acute exposure to many hepatotoxic agents including alcohol [110,111], APAP [112–116], arachidonic acid [117], 4-HNE and carbon tetrachloride [118], palmitic acid [119], and troglitazone [120] significantly activated JNK (p-JNK) and/or p38K (p-p38K), contributing to toxicity in a variety of cells.”
BackgroundWang, X., Wu, D., Yang, L., & Cederbaum, A. I. (2011) · Hepatology · doi:10.1002/hep.24540 · Cited by 19 · see citing works
- Authors
- Lee, Y. J., & Shukla, S. D.
- Affiliations
- University of Missouri (US)
- Corresponding author
- Shukla, Shivendra D.
- ORCID
- Lee, Youn Ju
- Venue
- European Journal of Pharmacology
- Publisher
- Elsevier BV
- Published
- 2005-01
- Volume
- 508
- Issue
- 1-3
- Pages
- 31-45
- ISSN
- 0014-2999 (ISSN-L)
- OpenAlex
- W2002240376
- Cited by
- 70
- References
- 66
- Citations by year
- 2024: 1 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 2 · 2018: 1 · 2017: 1 · 2015: 3 · 2014: 2 · 2013: 3 · 2012: 6
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (AA11962, R01AA011962)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- c-Jun N-terminal kinase, p44/42 MAPK, ethanol, acetaldehyde, hepatocyte apoptosis, SP600125, U0126, MKK1, caspase-3, genistein, protein kinase C, oxidative stress, alcohol-induced liver injury, MAPK signaling, JNK inhibitor, MAPK inhibitors
- MeSH terms
- Acetaldehyde, Acetylcysteine, Ethanol, Animals, Anthracenes, Butadienes, Cell Nucleus, Dose-Response Relationship, Drug, Enzyme Activation, Enzyme Inhibitors, Hydrogen Peroxide, Indoles, Male, Maleates, Maleimides, Microscopy, Fluorescence, Nitriles, Time Factors, Blotting, Western, Rats, Sprague-Dawley, Apoptosis, Reactive Oxygen Species, Buthionine Sulfoximine, Genistein, Mitogen-Activated Protein Kinase 1, Caspases, Hepatocytes, JNK Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 3, Rats, Caspase 3, DNA Fragmentation
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