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Science 286 (5443): 1358-1362

Copyright © 1999 by the American Association for the Advancement of Science

Cell Survival Promoted by the Ras-MAPK Signaling Pathway by Transcription-Dependent and -Independent Mechanisms

Azad Bonni, * Anne Brunet, Anne E. West, Sandeep Robert Datta, Mari A. Takasu, Michael E. Greenberg dagger

A mechanism by which the Ras-mitogen-activated protein kinase (MAPK) signaling pathway mediates growth factor-dependent cell survival was characterized. The MAPK-activated kinases, the Rsks, catalyzed the phosphorylation of the pro-apoptotic protein BAD at serine 112 both in vitro and in vivo. The Rsk-induced phosphorylation of BAD at serine 112 suppressed BAD-mediated apoptosis in neurons. Rsks also are known to phosphorylate the transcription factor CREB (cAMP response element-binding protein) at serine 133. Activated CREB promoted cell survival, and inhibition of CREB phosphorylation at serine 133 triggered apoptosis. These findings suggest that the MAPK signaling pathway promotes cell survival by a dual mechanism comprising the posttranslational modification and inactivation of a component of the cell death machinery and the increased transcription of pro-survival genes.

Division of Neuroscience, Children's Hospital, and Department of Neurobiology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
*   Present address: Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

dagger    To whom correspondence should be addressed. E-mail: greenberg{at}

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C/EBP phosphorylation rescues macrophage dysfunction and apoptosis induced by anthrax lethal toxin.
M. Buck and M. Chojkier (2007)
Am J Physiol Cell Physiol 293, C1788-C1796
   Abstract »    Full Text »    PDF »
Leptin Protects against 6-Hydroxydopamine-induced Dopaminergic Cell Death via Mitogen-activated Protein Kinase Signaling.
Z. Weng, A. P. Signore, Y. Gao, S. Wang, F. Zhang, T. Hastings, X.-M. Yin, and J. Chen (2007)
J. Biol. Chem. 282, 34479-34491
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Role of Kinase Suppressor of Ras-1 in Neuronal Survival Signaling by Extracellular Signal-Regulated Kinase 1/2.
E. Szatmari, K. B. Kalita, G. Kharebava, and M. Hetman (2007)
J. Neurosci. 27, 11389-11400
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Breast Cancer Cell Proliferation Is Inhibited by BAD: REGULATION OF CYCLIN D1.
R. Fernando, J. S. Foster, A. Bible, A. Strom, R. G. Pestell, M. Rao, A. Saxton, S. J. Baek, K. Yamaguchi, R. Donnell, et al. (2007)
J. Biol. Chem. 282, 28864-28873
   Abstract »    Full Text »    PDF »
Ribosomal S6 Kinase 2 Is a Key Regulator in Tumor Promoter Induced Cell Transformation.
Y.-Y. Cho, K. Yao, H.-G. Kim, B. S. Kang, D. Zheng, A. M. Bode, and Z. Dong (2007)
Cancer Res. 67, 8104-8112
   Abstract »    Full Text »    PDF »
Endocannabinoid Enhancement Protects against Kainic Acid-Induced Seizures and Associated Brain Damage.
D. A. Karanian, S. L. Karim, J. T. Wood, J. S. Williams, S. Lin, A. Makriyannis, and B. A. Bahr (2007)
J. Pharmacol. Exp. Ther. 322, 1059-1066
   Abstract »    Full Text »    PDF »
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 »
Hypoxia Inhibits Paclitaxel-Induced Apoptosis through Adenosine-Mediated Phosphorylation of Bad in Glioblastoma Cells.
S. Merighi, A. Benini, P. Mirandola, S. Gessi, K. Varani, E. Leung, S. Maclennan, P. G. Baraldi, and P. A. Borea (2007)
Mol. Pharmacol. 72, 162-172
   Abstract »    Full Text »    PDF »
ERK1/2-dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl-1 and Bcl-xL.
K. E. Ewings, K. Hadfield-Moorhouse, C. M. Wiggins, J. A. Wickenden, K. Balmanno, R. Gilley, K. Degenhardt, E. White, and S. J. Cook (2007)
EMBO J. 26, 2856-2867
   Abstract »    Full Text »    PDF »
Transcription factor Sp4 regulates dendritic patterning during cerebellar maturation.
B. Ramos, B. Gaudilliere, A. Bonni, and G. Gill (2007)
PNAS 104, 9882-9887
   Abstract »    Full Text »    PDF »
Erythropoietin promotes survival of primary human endothelial cells through PI3K-dependent, NF-{kappa}B-independent upregulation of Bcl-xL.
R. Zhande and A. Karsan (2007)
Am J Physiol Heart Circ Physiol 292, H2467-H2474
   Abstract »    Full Text »    PDF »
MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825.
T. K. Nguyen, M. Rahmani, H. Harada, P. Dent, and S. Grant (2007)
Blood 109, 4006-4015
   Abstract »    Full Text »    PDF »
CpG DNA Activates Survival in Murine Macrophages through TLR9 and the Phosphatidylinositol 3-Kinase-Akt Pathway.
D. P. Sester, K. Brion, A. Trieu, H. S. Goodridge, T. L. Roberts, J. Dunn, D. A. Hume, K. J. Stacey, and M. J. Sweet (2006)
J. Immunol. 177, 4473-4480
   Abstract »    Full Text »    PDF »
Epidermal Growth Factor Protects Prostate Cancer Cells from Apoptosis by Inducing BAD Phosphorylation via Redundant Signaling Pathways.
K. S. R. Sastry, Y. Karpova, and G. Kulik (2006)
J. Biol. Chem. 281, 27367-27377
   Abstract »    Full Text »    PDF »
{Delta}9-Tetrahydrocannabinol-Induced Apoptosis in Jurkat Leukemia T Cells Is Regulated by Translocation of Bad to Mitochondria.
W. Jia, V. L. Hegde, N. P. Singh, D. Sisco, S. Grant, M. Nagarkatti, and P. S. Nagarkatti (2006)
Mol. Cancer Res. 4, 549-562
   Abstract »    Full Text »    PDF »
Neural-specific inactivation of ShcA results in increased embryonic neural progenitor apoptosis and microencephaly..
K. N. McFarland, S. R. Wilkes, S. E. Koss, K. S. Ravichandran, and J. W. Mandell (2006)
J. Neurosci. 26, 7885-7897
   Abstract »    Full Text »    PDF »
Gene 33/RALT Is Induced by Hypoxia in Cardiomyocytes, Where It Promotes Cell Death by Suppressing Phosphatidylinositol 3-Kinase and Extracellular Signal-Regulated Kinase Survival Signaling.
D. Xu, R. D. Patten, T. Force, and J. M. Kyriakis (2006)
Mol. Cell. Biol. 26, 5043-5054
   Abstract »    Full Text »    PDF »
VEGF-C promotes survival in podocytes.
R. R. Foster, S. C. Satchell, J. Seckley, M. S. Emmett, K. Joory, C. Y. Xing, M. A. Saleem, P. W. Mathieson, D. O. Bates, and S. J. Harper (2006)
Am J Physiol Renal Physiol 291, F196-F207
   Abstract »    Full Text »    PDF »

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