Activation of the Pro-survival Phosphatidylinositol 3-Kinase/AKT Pathway by Transforming Growth Factor-β1 in Mesenchymal Cells Is Mediated by p38 MAPK-dependent Induction of an Autocrine Growth Factor
| Autor: | Zongbin Cui, Jeffrey C. Horowitz, Meghna Waghray, Venkateshwar G. Keshamouni, Daniel Y. Lee, Victor J. Thannickal, Hengmin Zhang, Peedikayil E. Thomas |
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| Rok vydání: | 2004 |
| Předmět: |
Time Factors
Pyridines medicine.medical_treatment Apoptosis p38 Mitogen-Activated Protein Kinases Biochemistry Mesoderm Phosphatidylinositol 3-Kinases Transforming Growth Factor beta Enzyme Inhibitors Phosphorylation Growth Substances Lung Cells Cultured biology Caspase 3 Imidazoles Cell biology Phenotype Cytokine Caspases Cytokines Mitogen-Activated Protein Kinases Signal transduction Cell Division Plasmids Signal Transduction Cell Survival Blotting Western DNA Single-Stranded Enzyme-Linked Immunosorbent Assay Models Biological Article Transforming Growth Factor beta1 Transforming Growth Factor beta2 medicine Humans Autocrine signalling Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Dose-Response Relationship Drug Akt/PKB signaling pathway Cell Biology Transforming growth factor beta Fibroblasts Enzyme Activation Microscopy Fluorescence Culture Media Conditioned Mutation biology.protein Densitometry Transforming growth factor |
| Zdroj: | Journal of Biological Chemistry. 279:1359-1367 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m306248200 |
| Popis: | Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine involved in differentiation, growth, and survival of mesenchymal cells while inhibiting growth/survival of most other cell types. The mechanism(s) of pro-survival signaling by TGF-beta1 in mesenchymal cells is unclear. In this report, we demonstrate that TGF-beta1 protects against serum deprivation-induced apoptosis of mesenchymal cells isolated from patients with acute lung injury and of normal human fetal lung fibroblasts (IMR-90). TGF-beta receptor(s)-activated signaling in these cells involves rapid activation of the Smad and p38 MAPK pathways within minutes of TGF-beta1 treatment followed by a more delayed activation of the pro-survival phosphatidylinositol 3-kinase-protein kinase B (PKB)/Akt pathway. Pharmacological inhibition of p38 MAPK with SB203580 or expression of a p38 kinase-deficient mutant protein inhibits TGF-beta1-induced PKB/Akt phosphorylation. Conditioned medium from TGF-beta1-treated cells rapidly induces PKB/Akt activation in an SB203580- and suramin-sensitive manner, suggesting p38 MAPK-dependent production of a secreted growth factor that activates this pro-survival pathway by an autocrine/paracrine mechanism. Inhibition of the phosphatidylinositol 3-kinase-PKB/Akt pathway blocks TGF-beta1-induced resistance to apoptosis. These results demonstrate the activation of a novel TGF-beta1-activated pro-survival/anti-apoptotic signaling pathway in mesenchymal cells/fibroblasts that may explain cell-specific actions of TGF-beta1 and provide mechanistic insights into its pro-fibrotic and tumor-promoting effects. |
| Databáze: | OpenAIRE |
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