 |
|||||
|
|||||
|
|||||
|
|||||
|
|||||
Previous Article | Next Article
The Journal of Neuroscience, June 1, 1998, 18(11):4042-4049
Prevention of PC12 Cell Death by N-Acetylcysteine Requires Activation of the Ras Pathway
Chao Yun Irene Yan and Lloyd A. Greene Center for Neurobiology and Behavior and Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York 10032
We have shown that N-acetylcysteine (NAC) promotes survival of sympathetic neurons and pheochromocytoma (PC12) cells in the absence of trophic factors. This action of NAC was not related to its antioxidant properties or ability to increase intracellular glutathione levels but was instead dependent on ongoing transcription and seemed attributable to the action of NAC as a reducing agent. Here, we investigate the mechanism by which NAC promotes neuronal survival. We show that NAC activates the Ras-extracellular signal-regulated kinase (ERK) pathway in PC12 cells. Ras activation by NAC seems necessary for survival in that it is unable to sustain serum-deprived PC12 MM17-26 cells constitutively expressing a dominant-negative form of Ras. Promotion of PC12 cell survival by NAC is totally blocked by PD98059, an inhibitor of the ERK-activating MAP kinase/ERK kinase, suggesting a required role for ERK activation in the NAC mechanism. In contrast, LY294002 and wortmannin, inhibitors of phosphatidylinositol 3-kinase (PI3K) that partially block NGF-promoted PC12 cell survival, have no effect on prevention of death by NAC. We hypothesized previously that the ability of NAC to promote survival correlates with its antiproliferative properties. However, although NAC does not protect PC12 MM17-26 cells from loss of trophic support, it does inhibit their capacity to synthesize DNA. Thus, the antiproliferative effect of NAC does not require Ras activation, and inhibition of DNA synthesis is insufficient to mediate NAC-promoted survival. These findings highlight the role of Ras-ERK activation in the mechanism by which NAC prevents neuronal death after loss of trophic support.
Key words: apoptosis; neuronal survival; N-acetylcysteine; Ras; cell cycle; trophic factor withdrawal
Copyright © 1998 Society for Neuroscience 0270-6474/98/18114042-08$05.00/0
This article has been cited by other articles:
T.-M. Lee, P.-Y. Lai, and N.-C. Chang
Effect of N-acetylcysteine on sympathetic hyperinnervation in post-infarcted rat hearts
Cardiovasc Res, September 16, 2009; (2009) cvp286v2.
[Abstract] [Full Text] [PDF]
P. Bhoopathi, C. Chetty, S. Kunigal, S. K. Vanamala, J. S. Rao, and S. S. Lakka
Blockade of Tumor Growth Due to Matrix Metalloproteinase-9 Inhibition Is Mediated by Sequential Activation of 1-Integrin, ERK, and NF-{kappa}B
J. Biol. Chem., January 18, 2008; 283(3): 1545 - 1552.
[Abstract] [Full Text] [PDF]
S. Dhingra, A. K. Sharma, D. K. Singla, and P. K. Singal
p38 and ERK1/2 MAPKs mediate the interplay of TNF-{alpha} and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis
Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3524 - H3531.
[Abstract] [Full Text] [PDF]
C. Malagelada, E. J. Ryu, S. C. Biswas, V. Jackson-Lewis, and L. A. Greene
RTP801 Is Elevated in Parkinson Brain Substantia Nigral Neurons and Mediates Death in Cellular Models of Parkinson's Disease by a Mechanism Involving Mammalian Target of Rapamycin Inactivation
J. Neurosci., September 27, 2006; 26(39): 9996 - 10005.
[Abstract] [Full Text] [PDF]
E. Rosati, R. Sabatini, E. Ayroldi, A. Tabilio, A. Bartoli, S. Bruscoli, C. Simoncelli, R. Rossi, and P. Marconi
Apoptosis of human primary B lymphocytes is inhibited by N-acetyl-L-cysteine
J. Leukoc. Biol., July 1, 2004; 76(1): 152 - 161.
[Abstract] [Full Text] [PDF]
V. D. Nair, T. Yuen, C. W. Olanow, and S. C. Sealfon
Early Single Cell Bifurcation of Pro- and Antiapoptotic States during Oxidative Stress
J. Biol. Chem., June 25, 2004; 279(26): 27494 - 27501.
[Abstract] [Full Text] [PDF]
S. Bhattacharya, R. M. Ray, and L. R. Johnson
Prevention of TNF-{alpha}-induced apoptosis in polyamine-depleted IEC-6 cells is mediated through the activation of ERK1/2
Am J Physiol Gastrointest Liver Physiol, March 1, 2004; 286(3): G479 - G490.
[Abstract] [Full Text] [PDF]
M.-T. Park, J.-A Choi, M.-J. Kim, H.-D. Um, S. Bae, C.-M. Kang, C.-K. Cho, S. Kang, H. Y. Chung, Y.-S. Lee, et al.
Suppression of Extracellular Signal-related Kinase and Activation of p38 MAPK Are Two Critical Events Leading to Caspase-8- and Mitochondria-mediated Cell Death in Phytosphingosine-treated Human Cancer Cells
J. Biol. Chem., December 12, 2003; 278(50): 50624 - 50634.
[Abstract] [Full Text] [PDF]
J. L. Berkeley and A. I. Levey
Cell-Specific Extracellular Signal-Regulated Kinase Activation by Multiple G Protein-Coupled Receptor Families in Hippocampus
Mol. Pharmacol., January 1, 2003; 63(1): 128 - 135.
[Abstract] [Full Text] [PDF]
D. Perkins, E. F. R. Pereira, and L. Aurelian
The Herpes Simplex Virus Type 2 R1 Protein Kinase (ICP10 PK) Functions as a Dominant Regulator of Apoptosis in Hippocampal Neurons Involving Activation of the ERK Survival Pathway and Upregulation of the Antiapoptotic Protein Bag-1
J. Virol., December 20, 2002; 77(2): 1292 - 1305.
[Abstract] [Full Text] [PDF]
S. C. Biswas and L. A. Greene
Nerve Growth Factor (NGF) Down-regulates the Bcl-2 Homology 3 (BH3) Domain-only Protein Bim and Suppresses Its Proapoptotic Activity by Phosphorylation
J. Biol. Chem., December 13, 2002; 277(51): 49511 - 49516.
[Abstract] [Full Text] [PDF]
M. Hetman, S.-L. Hsuan, A. Habas, M. J. Higgins, and Z. Xia
ERK1/2 Antagonizes Glycogen Synthase Kinase-3beta -induced Apoptosis in Cortical Neurons
J. Biol. Chem., December 13, 2002; 277(51): 49577 - 49584.
[Abstract] [Full Text] [PDF]
B. A. Ballif and J. Blenis
Molecular Mechanisms Mediating Mammalian Mitogen-activated Protein Kinase (MAPK) Kinase (MEK)-MAPK Cell Survival Signals
Cell Growth Differ., August 1, 2001; 12(8): 397 - 408.
[Full Text] [PDF]
E. D. Chan, D. W. H. Riches, and C. W. White
Redox Paradox: Effect of N-Acetylcysteine and Serum on Oxidation Reduction-Sensitive Mitogen-Activated Protein Kinase Signaling Pathways
Am. J. Respir. Cell Mol. Biol., May 1, 2001; 24(5): 627 - 632.
[Abstract] [Full Text]
M. R. Hansen, X.-M. Zha, J. Bok, and S. H. Green
Multiple Distinct Signal Pathways, Including an Autocrine Neurotrophic Mechanism, Contribute to the Survival-Promoting Effect of Depolarization on Spiral Ganglion Neurons In Vitro
J. Neurosci., April 1, 2001; 21(7): 2256 - 2267.
[Abstract] [Full Text] [PDF]
R. A. Kirkland and J. L. Franklin
Evidence for Redox Regulation of Cytochrome c Release during Programmed Neuronal Death: Antioxidant Effects of Protein Synthesis and Caspase Inhibition
J. Neurosci., March 15, 2001; 21(6): 1949 - 1963.
[Abstract] [Full Text] [PDF]
D. Sulzer, J. Bogulavsky, K. E. Larsen, G. Behr, E. Karatekin, M. H. Kleinman, N. Turro, D. Krantz, R. H. Edwards, L. A. Greene, et al.
Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles
PNAS, October 24, 2000; 97(22): 11869 - 11874.
[Abstract] [Full Text] [PDF]
J. R. Wu-Wong, W. J. Chiou, and J. Wang
Extracellular Signal-Regulated Kinases Are Involved in the Antiapoptotic Effect of Endothelin-1
J. Pharmacol. Exp. Ther., May 1, 2000; 293(2): 514 - 521.
[Abstract] [Full Text]
B. Jiang and P. Brecher
N-Acetyl-L-Cysteine Potentiates Interleukin-1{beta} Induction of Nitric Oxide Synthase : Role of p44/42 Mitogen-Activated Protein Kinases
Hypertension, April 1, 2000; 35(4): 914 - 918.
[Abstract] [Full Text] [PDF]
M. Hetman, K. Kanning, J. E. Cavanaugh, and Z. Xia
Neuroprotection by Brain-derived Neurotrophic Factor Is Mediated by Extracellular Signal-regulated Kinase and Phosphatidylinositol 3-Kinase
J. Biol. Chem., August 6, 1999; 274(32): 22569 - 22580.
[Abstract] [Full Text] [PDF]
P. Erhardt, E. J. Schremser, and G. M. Cooper
B-Raf Inhibits Programmed Cell Death Downstream of Cytochrome c Release from Mitochondria by Activating the MEK/Erk Pathway
Mol. Cell. Biol., August 1, 1999; 19(8): 5308 - 5315.
[Abstract] [Full Text] [PDF]
S. Buckley, B. Driscoll, L. Barsky, K. Weinberg, K. Anderson, and D. Warburton
ERK activation protects against DNA damage and apoptosis in hyperoxic rat AEC2
Am J Physiol Lung Cell Mol Physiol, July 1, 1999; 277(1): L159 - L166.
[Abstract] [Full Text] [PDF]
W.-N. Tian, L. D. Braunstein, K. Apse, J. Pang, M. Rose, X. Tian, and R. C. Stanton
Importance of glucose-6-phosphate dehydrogenase activity in cell death
Am J Physiol Cell Physiol, May 1, 1999; 276(5): C1121 - C1131.
[Abstract] [Full Text] [PDF]
B. Murray, A. Alessandrini, A. J. Cole, A. G. Yee, and E. J. Furshpan
Inhibition of the p44/42 MAP kinase pathway protects hippocampal neurons in a cell-culture model of seizure activity
PNAS, September 29, 1998; 95(20): 11975 - 11980.
[Abstract] [Full Text] [PDF]
P. Z. Anastasiadis, H. Jiang, L. Bezin, D. M. Kuhn, and R. A. Levine
Tetrahydrobiopterin Enhances Apoptotic PC12 Cell Death following Withdrawal of Trophic Support
J. Biol. Chem., March 16, 2001; 276(12): 9050 - 9058.
[Abstract] [Full Text] [PDF]
S. E. Hamilton and N. M. Nathanson
The M1 Receptor Is Required for Muscarinic Activation of Mitogen-activated Protein (MAP) Kinase in Murine Cerebral Cortical Neurons
J. Biol. Chem., May 4, 2001; 276(19): 15850 - 15853.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|