GAS6‐induced signaling in human endothelial cells is mediated by FOXO1a
| Autor: | Md. Ruhul Abid, J. G. Ganopolsky, Mark Blostein, William C. Aird |
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| Rok vydání: | 2008 |
| Předmět: |
Umbilical Veins
Transcription Genetic Endothelium Cell Survival Active Transport Cell Nucleus Down-Regulation Biology Wortmannin Phosphatidylinositol 3-Kinases chemistry.chemical_compound Downregulation and upregulation medicine Humans Phosphorylation Protein kinase B PI3K/AKT/mTOR pathway Forkhead Box Protein O1 Endothelial Cells Forkhead Transcription Factors Hematology Cell biology Kinetics Vascular endothelial growth factor A medicine.anatomical_structure chemistry Apoptosis Cancer research Intercellular Signaling Peptides and Proteins Cyclin-Dependent Kinase Inhibitor p27 Signal Transduction |
| Zdroj: | Journal of Thrombosis and Haemostasis. 6:1804-1811 |
| ISSN: | 1538-7836 |
| Popis: | Summary. Background: Growth Arrest Specific gene product 6 (gas6) is a γ-carboxylated protein that protects endothelial cells against apoptosis. Gas6 has previously been shown to induce phospatidyl-3-inositol-kinase (PI3K)/Akt signaling. Other studies have demonstrated a link between PI3K/Akt signaling and forkhead transcription factors in endothelial cells. Objective: To test the hypothesis that gas6 promotes cell survival via a forkhead-dependent pathway. Results and Conclusions: Treatment of serum-starved human umbilical vein endothelial cells (HUVECs) with gas6 induced time-dependent phosphorylation and nuclear exclusion of FOXO1a. This effect was suppressed by the PI3K inhibitor wortmannin, demonstrating that FOXO1a phosphorylation is PI3-kinase dependent. Transduction of HUVECs with a phosphorylation-resistant form of FOXO1a [triple mutant (TM)-FOXO1a] abrogated the pro-survival effect of gas6 on serum-starved endothelial cells. Finally, treatment of serum-starved HUVECs with gas6 resulted in a reduction of FOXO1a transcriptional activity and downregulation of the pro-apoptotic gene, p27kip1. Taken together, these findings suggest that gas6 protects endothelial cells from apoptosis by a mechanism that involves PI3K-Akt-dependent inactivation of FOXO1a. |
| Databáze: | OpenAIRE |
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