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

• Published in: Science (American Association for the Advancement of Science) Vol. 286; no. 5443; pp. 1358 - 1362
• Main Authors: Bonni, Azad, Brunet, Anne, West, Anne E., Datta, Sandeep Robert, Takasu, Mari A., Greenberg, Michael E.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for the Advancement of Science 12-11-1999; American Association for the Advancement of Science; The American Association for the Advancement of Science
• Subjects: Animals; Antibodies; Apoptosis; bcl-Associated Death Protein; Biological and medical sciences; Brain-Derived Neurotrophic Factor - pharmacology; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell death; Cell growth; Cell physiology; Cell Survival; Cells; Cells, Cultured; Cellular biology; Cerebellum - cytology; Cyclic AMP Response Element-Binding Protein - metabolism; Enzyme Activation; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Fundamental and applied biological sciences. Psychology; Genes; Immunoblotting; Inhibition; Insulin-Like Growth Factor I - pharmacology; MAP Kinase Kinase 1; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Molecular and cellular biology; Mutation; Neurons; Neurons - cytology; Neurons - metabolism; Neuroscience; Phosphorylation; Phosphoserine - metabolism; Plasmids; Protein kinases; Protein-Serine-Threonine Kinases; Proteins; ras Proteins - metabolism; Rats; Rats, Long-Evans; Recombinant Fusion Proteins - metabolism; Ribosomal Protein S6 Kinases - genetics; Ribosomal Protein S6 Kinases - metabolism; Signal transduction; Transcription, Genetic; Transfection; Human; Phosphorylation; Enzyme; Transferases; Serine; Survival; Protein; Kidney; Signal transduction; Cell line; Neuron; Gene; Protein kinase; Cell; Transcription factor CREB; Apoptosis
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.286.5443.1358

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.