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Previous Article | Next Article
The Journal of Neuroscience, April 15, 1998, 18(8):2933-2943
Phosphatidylinositol 3-Kinase and Akt Protein Kinase Are Necessary and Sufficient for the Survival of Nerve Growth Factor-Dependent Sympathetic Neurons
Robert J. Crowder and Robert S. Freeman Department of Pharmacology and Physiology, University of Rochester, School of Medicine, Rochester, New York 14642
Recent studies have suggested a role for phosphatidylinositol (PI) 3-kinase in cell survival, including the survival of neurons. We used rat sympathetic neurons maintained in vitro to characterize the potential survival signals mediated by PI 3-kinase and to test whether the Akt protein kinase, a putative effector of PI 3-kinase, functions during nerve growth factor (NGF)-mediated survival. Two PI 3-kinase inhibitors, LY294002 and wortmannin, block NGF-mediated survival of sympathetic neurons. Cell death caused by LY294002 resembles death caused by NGF deprivation in that it is blocked by a caspase inhibitor or a cAMP analog and that it is accompanied by the induction of c-jun, c-fos, and cyclin D1 mRNAs. Treatment of neurons with NGF activates endogenous Akt protein kinase, and LY294002 or wortmannin blocks this activation. Expression of constitutively active Akt or PI 3-kinase in neurons efficiently prevents death after NGF withdrawal. Conversely, expression of dominant negative forms of PI 3-kinase or Akt induces apoptosis in the presence of NGF. These results demonstrate that PI 3-kinase and Akt are both necessary and sufficient for the survival of NGF-dependent sympathetic neurons.
Key words: apoptosis; phosphatidylinositol 3-kinase; NGF; neuronal survival; Akt; neurotrophic factor
Copyright © 1998 Society for Neuroscience 0270-6474/98/1882933-11$05.00/0
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R. E. Bachelder, M. J. Ribick, A. Marchetti, R. Falcioni, S. Soddu, K. R. Davis, and A. M. Mercurio
P53 Inhibits {alpha}6{beta}4 Integrin Survival Signaling by Promoting the Caspase 3-Dependent Cleavage of Akt/PKB
J. Cell Biol., November 29, 1999; 147(5): 1063 - 1072.
[Abstract] [Full Text] [PDF]
I. E. Mazzoni, F. A. Said, R. Aloyz, F. D. Miller, and D. Kaplan
Ras Regulates Sympathetic Neuron Survival by Suppressing the p53-Mediated Cell Death Pathway
J. Neurosci., November 15, 1999; 19(22): 9716 - 9727.
[Abstract] [Full Text] [PDF]
S. R. Datta, A. Brunet, and M. E. Greenberg
Cellular survival: a play in three Akts
Genes & Dev., November 15, 1999; 13(22): 2905 - 2927.
[Full Text]
R. M. Soler, X. Dolcet, M. Encinas, J. Egea, J. R. Bayascas, and J. X. Comella
Receptors of the Glial Cell Line-Derived Neurotrophic Factor Family of Neurotrophic Factors Signal Cell Survival through the Phosphatidylinositol 3-Kinase Pathway in Spinal Cord Motoneurons
J. Neurosci., November 1, 1999; 19(21): 9160 - 9169.
[Abstract] [Full Text] [PDF]
A.R. Vaillant, I. Mazzoni, C. Tudan, M. Boudreau, D.R. Kaplan, and F.D. Miller
Depolarization and Neurotrophins Converge on the Phosphatidylinositol 3-Kinase-Akt Pathway to Synergistically Regulate Neuronal Survival
J. Cell Biol., September 6, 1999; 146(5): 955 - 966.
[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]
J. Lin, R. M. Adam, E. Santiestevan, and M. R. Freeman
The Phosphatidylinositol 3'-kinase Pathway Is a Dominant Growth Factor-activated Cell Survival Pathway in LNCaP Human Prostate Carcinoma Cells
Cancer Res., June 1, 1999; 59(12): 2891 - 2897.
[Abstract] [Full Text] [PDF]
S. S. Kang, T. Kwon, D. Y. Kwon, and S. I. Do
Akt Protein Kinase Enhances Human Telomerase Activity through Phosphorylation of Telomerase Reverse Transcriptase Subunit
J. Biol. Chem., May 7, 1999; 274(19): 13085 - 13090.
[Abstract] [Full Text] [PDF]
S. Heck, F. Lezoualc'h, S. Engert, and C. Behl
Insulin-like Growth Factor-1-mediated Neuroprotection against Oxidative Stress Is Associated with Activation of Nuclear Factor kappa B
J. Biol. Chem., April 2, 1999; 274(14): 9828 - 9835.
[Abstract] [Full Text] [PDF]
N. Farrelly, Y.-J. Lee, J. Oliver, C. Dive, and C. H. Streuli
Extracellular Matrix Regulates Apoptosis in Mammary Epithelium through a Control on Insulin Signaling
J. Cell Biol., March 22, 1999; 144(6): 1337 - 1348.
[Abstract] [Full Text] [PDF]
L. A. C. Blair, K. K. Bence-Hanulec, S. Mehta, T. Franke, D. Kaplan, and J. Marshall
Akt-Dependent Potentiation of L Channels by Insulin-Like Growth Factor-1 Is Required for Neuronal Survival
J. Neurosci., March 15, 1999; 19(6): 1940 - 1951.
[Abstract] [Full Text] [PDF]
M. P. Allen, C. Zeng, K. Schneider, X. Xiong, M. K. Meintzer, P. Bellosta, C. Basilico, B. Varnum, K. A. Heidenreich, and M. E. Wierman
Growth Arrest-Specific Gene 6 (Gas6)/Adhesion Related Kinase (Ark) Signaling Promotes Gonadotropin-Releasing Hormone Neuronal Survival via Extracellular Signal-Regulated Kinase (ERK) and Akt
Mol. Endocrinol., February 1, 1999; 13(2): 191 - 201.
[Abstract] [Full Text]
C. N. G. Anderson and A. M. Tolkovsky
A Role for MAPK/ERK in Sympathetic Neuron Survival: Protection against a p53-Dependent, JNK-Independent Induction of Apoptosis by Cytosine Arabinoside
J. Neurosci., January 15, 1999; 19(2): 664 - 673.
[Abstract] [Full Text] [PDF]
S. B. Maggirwar, P. D. Sarmiere, S. Dewhurst, and R. S. Freeman
Nerve Growth Factor-Dependent Activation of NF-kappa B Contributes to Survival of Sympathetic Neurons
J. Neurosci., December 15, 1998; 18(24): 10356 - 10365.
[Abstract] [Full Text] [PDF]
L. J. Klesse and L. F. Parada
p21 Ras and Phosphatidylinositol-3 Kinase Are Required for Survival of Wild-Type and NF1 Mutant Sensory Neurons
J. Neurosci., December 15, 1998; 18(24): 10420 - 10428.
[Abstract] [Full Text] [PDF]
M. A. Vogelbaum, J. X. Tong, and K. M. Rich
Developmental Regulation of Apoptosis in Dorsal Root Ganglion Neurons
J. Neurosci., November 1, 1998; 18(21): 8928 - 8935.
[Abstract] [Full Text] [PDF]
W. Wu, W.-L. Lee, Y. Y. Wu, D. Chen, T.-J. Liu, A. Jang, P. M. Sharma, and P. H. Wang
Expression of Constitutively Active Phosphatidylinositol 3-Kinase Inhibits Activation of Caspase 3 and Apoptosis of Cardiac Muscle Cells
J. Biol. Chem., December 15, 2000; 275(51): 40113 - 40119.
[Abstract] [Full Text] [PDF]
Y. Xie, M. A. Tisi, T. T. Yeo, and F. M. Longo
Nerve Growth Factor (NGF) Loop 4 Dimeric Mimetics Activate ERK and AKT and Promote NGF-like Neurotrophic Effects
J. Biol. Chem., September 15, 2000; 275(38): 29868 - 29874.
[Abstract] [Full Text] [PDF]
R. J. Crowder and R. S. Freeman
Glycogen Synthase Kinase-3beta Activity Is Critical for Neuronal Death Caused by Inhibiting Phosphatidylinositol 3-Kinase or Akt but Not for Death Caused by Nerve Growth Factor Withdrawal
J. Biol. Chem., October 27, 2000; 275(44): 34266 - 34271.
[Abstract] [Full Text] [PDF]
V. Besset, R. P. Scott, and C. F. Ibanez
Signaling Complexes and Protein-Protein Interactions Involved in the Activation of the Ras and Phosphatidylinositol 3-Kinase Pathways by the c-Ret Receptor Tyrosine Kinase
J. Biol. Chem., December 8, 2000; 275(50): 39159 - 39166.
[Abstract] [Full Text] [PDF]
E. A. Lipscomb, P. D. Sarmiere, and R. S. Freeman
SM-20 Is a Novel Mitochondrial Protein That Causes Caspase-dependent Cell Death in Nerve Growth Factor-dependent Neurons
J. Biol. Chem., February 9, 2001; 276(7): 5085 - 5092.
[Abstract] [Full Text] [PDF]
A. Yamaguchi, M. Tamatani, H. Matsuzaki, K. Namikawa, H. Kiyama, M. P. Vitek, N. Mitsuda, and M. Tohyama
Akt Activation Protects Hippocampal Neurons from Apoptosis by Inhibiting Transcriptional Activity of p53
J. Biol. Chem., February 9, 2001; 276(7): 5256 - 5264.
[Abstract] [Full Text] [PDF]
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