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Science 24 November 1995:
Vol. 270. no. 5240, pp. 1326 - 1331
DOI: 10.1126/science.270.5240.1326
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Research Articles

Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis

Zhengui Xia,  Martin Dickens,  Joël Raingeaud,  Roger J. Davis,  Michael E. Greenberg (1)

Apoptosis plays an important role during neuronal development, and defects in apoptosis may underlie various neurodegenerative disorders. To characterize molecular mechanisms that regulate neuronal apoptosis, the contributions to cell death of mitogen-activated protein (MAP) kinase family members, including ERK (extracellular signal-regulated kinase), JNK (c-JUN NH(2)-terminal protein kinase), and p38, were examined after withdrawal of nerve growth factor (NGF) from rat PC-12 pheochromocytoma cells. NGF withdrawal led to sustained activation of the JNK and p38 enzymes and inhibition of ERKs. The effects of dominant-interfering or constitutively activated forms of various components of the JNK-p38 and ERK signaling pathways demonstrated that activation of JNK and p38 and concurrent inhibition of ERK are critical for induction of apoptosis in these cells. Therefore, the dynamic balance between growth factor-activated ERK and stress-activated JNK-p38 pathways may be important in determining whether a cell survives or undergoes apoptosis.


Z. Xia and M. E. Greenberg are in the Division of Neuroscience, Department of Neurology, Children's Hospital, and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. M. Dickens, J. Raingeaud, and R. J. Davis are in the Howard Hughes Medical Institute and Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
(1) To whom correspondence should be addressed.


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Grb10 and Active Raf-1 Kinase Promote Bad-dependent Cell Survival.
S. Kebache, J. Ash, M. G. Annis, J. Hagan, M. Huber, J. Hassard, C. L. Stewart, M. Whiteway, and A. Nantel (2007)
J. Biol. Chem. 282, 21873-21883
   Abstract »    Full Text »    PDF »
Critical role of c-jun (NH2) terminal kinase in paracetamol- induced acute liver failure.
N. C Henderson, K. J Pollock, J. Frew, A. C Mackinnon, R. A Flavell, R. J Davis, T. Sethi, and K. J Simpson (2007)
Gut 56, 982-990
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Using hyperosmolar stress to measure biologic and stress-activated protein kinase responses in preimplantation embryos.
Y. Xie, W. Zhong, Y. Wang, A. Trostinskaia, F. Wang, E.E. Puscheck, and D.A. Rappolee (2007)
Mol. Hum. Reprod. 13, 473-481
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Evidence That Curcumin Suppresses the Growth of Malignant Gliomas in Vitro and in Vivo through Induction of Autophagy: Role of Akt and Extracellular Signal-Regulated Kinase Signaling Pathways.
H. Aoki, Y. Takada, S. Kondo, R. Sawaya, B. B. Aggarwal, and Y. Kondo (2007)
Mol. Pharmacol. 72, 29-39
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A Molecular Link between E2F-1 and the MAPK Cascade.
J. Wang, W. H. Shen, Y. J. Jin, P. W. Brandt-Rauf, and Y. Yin (2007)
J. Biol. Chem. 282, 18521-18531
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Human Tribbles-1 Controls Proliferation and Chemotaxis of Smooth Muscle Cells via MAPK Signaling Pathways.
H. Y. Sung, H. Guan, A. Czibula, A. R. King, K. Eder, E. Heath, S. K. Suvarna, S. K. Dower, A. G. Wilson, S. E. Francis, et al. (2007)
J. Biol. Chem. 282, 18379-18387
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Intersectin-1s Regulates the Mitochondrial Apoptotic Pathway in Endothelial Cells.
S. A. Predescu, D. N. Predescu, I. Knezevic, I. K. Klein, and A. B. Malik (2007)
J. Biol. Chem. 282, 17166-17178
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H2S, Endoplasmic Reticulum Stress, and Apoptosis of Insulin-secreting Beta Cells.
G. Yang, W. Yang, L. Wu, and R. Wang (2007)
J. Biol. Chem. 282, 16567-16576
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Statins synergistically potentiate 7-hydroxystaurosporine (UCN-01) lethality in human leukemia and myeloma cells by disrupting Ras farnesylation and activation.
Y. Dai, P. Khanna, S. Chen, X.-Y. Pei, P. Dent, and S. Grant (2007)
Blood 109, 4415-4423
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Activation of c-Jun N-Terminal Protein Kinase Is a Common Mechanism Underlying Paraquat- and Rotenone-Induced Dopaminergic Cell Apoptosis.
H. Klintworth, K. Newhouse, T. Li, W.-S. Choi, R. Faigle, and Z. Xia (2007)
Toxicol. Sci. 97, 149-162
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Sulforaphane sensitizes tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis through downregulation of ERK and Akt in lung adenocarcinoma A549 cells.
C.-Y. Jin, D.-O. Moon, J.-D. Lee, M.-S. Heo, Y. H. Choi, C.-M. Lee, Y.-M. Park, and G.-Y. Kim (2007)
Carcinogenesis 28, 1058-1066
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Molecular Signalling Mediating the Protective Effect of A1 Adenosine and mGlu3 Metabotropic Glutamate Receptor Activation against Apoptosis by Oxygen/Glucose Deprivation in Cultured Astrocytes.
R. Ciccarelli, I. D'Alimonte, P. Ballerini, M. D'Auro, E. Nargi, S. Buccella, P. Di Iorio, V. Bruno, F. Nicoletti, and F. Caciagli (2007)
Mol. Pharmacol. 71, 1369-1380
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Regulation of the G2-M cell cycle progression by the ERK5-NF{kappa}B signaling pathway.
K. Cude, Y. Wang, H.-J. Choi, S.-L. Hsuan, H. Zhang, C.-Y. Wang, and Z. Xia (2007)
J. Cell Biol. 177, 253-264
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Inhibition of the MEK/ERK pathway reduces microglial activation and interleukin-1-beta expression in spinal cord ischemia/reperfusion injury in rats.
K. Lu, C.-L. Cho, C.-L. Liang, S.-D. Chen, P.-C. Liliang, S.-Y. Wang, and H.-J. Chen (2007)
J. Thorac. Cardiovasc. Surg. 133, 934-941
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In Vitro Toxicity of Tetrabromobisphenol-A on Cerebellar Granule Cells: Cell Death, Free Radical Formation, Calcium Influx and Extracellular Glutamate.
T. Reistad, E. Mariussen, A. Ring, and F. Fonnum (2007)
Toxicol. Sci. 96, 268-278
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PKC-{alpha} and TAK-1 are intermediates in the activation of c-Jun NH2-terminal kinase by hypoxia-reoxygenation.
D. P. Frazier, A. Wilson, C. J. Dougherty, H. Li, N. H. Bishopric, and K. A. Webster (2007)
Am J Physiol Heart Circ Physiol 292, H1675-H1684
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Ionotropic Stress and Integrin: Another Link to Myocardial Remodeling.
S. Pokharel and U. C. Sharma (2007)
Hypertension 49, 767-768
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Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase.
Y.-S. Choi, S. L. Lin, B. Lee, P. Kurup, H.-Y. Cho, J. R. Naegele, P. J. Lombroso, and K. Obrietan (2007)
J. Neurosci. 27, 2999-3009
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p38 Mitogen-Activated Protein Kinase Inhibition Ameliorates Angiotensin II-Induced Target Organ Damage.
J.-K. Park, R. Fischer, R. Dechend, E. Shagdarsuren, A. Gapeljuk, M. Wellner, S. Meiners, P. Gratze, N. Al-Saadi, S. Feldt, et al. (2007)
Hypertension 49, 481-489
   Abstract »    Full Text »    PDF »
The Protective Role of a Small GTPase RhoE against UVB-induced DNA Damage in Keratinocytes.
S. A. Boswell, P. P. Ongusaha, P. Nghiem, and S. W. Lee (2007)
J. Biol. Chem. 282, 4850-4858
   Abstract »    Full Text »    PDF »


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