Constitutively active STAT5 variants induce growth and survival of hematopoietic cells through a PI 3-kinase/Akt dependent pathway.
Signal Transducer and Activator of Transcription (STATs) are important mediators of cytokine and growth factor-induced signal transduction. STAT5A and STAT5B have been shown to play a role in survival and proliferation of hematopoietic cells both in vitro and in vivo and to contribute to the growth and viability of cells transformed by the TEL-JAK2 oncoprotein. In this study, we investigated the molecular mechanisms by which constitutively active STAT5 proteins induce cell proliferation and survival of Ba/F3 cell lines expressing either dominant positive STAT5A or STAT5B variants or TEL-JAK2 or TEL-ABL fusion proteins. Our results showed that active STAT5 constitutively interacted with p85, the regulatory subunit of the PI 3-kinase. A constitutive activity of the PI 3-kinase/Akt pathway was observed in these cells and required for their cell cycle progression. In contrast, while activity of the PI 3-kinase/Akt pathway was required for survival of Ba/F3 cells expressing the constitutively active forms of STAT5A or STAT5B, it was dispensable for cells transformed by TEL-JAK2 or TEL-ABL fusion proteins, suggesting that additional survival pathways take place in these transformed cells.
Santos
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SC
Institut Cochin de Génétique Moléculaire (ICGM), Institut National de la Santé et de la Recherche Médicale (INSERM U363), Hôpital Cochin, 27 rue du Fbg St Jacques, 75014 Paris, France.
Lacronique
V
V
Bouchaert
I
I
Monni
R
R
Bernard
O
O
Gisselbrecht
S
S
Gouilleux
F
F
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation; D004921:Erythropoietin / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology; D006801:Humans; D051379:Mice; D008894:Milk Proteins; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014170:Transformation, Genetic; D025521:Tumor Suppressor Proteins; D000097764:ETS Translocation Variant 6 Protein; D053614:Janus Kinase 2
D004268:DNA-Binding Proteins; D004921:Erythropoietin; D016044:Fusion Proteins, bcr-abl; D008894:Milk Proteins; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; C494092:STAT5A protein, human; C494095:STAT5B protein, human; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; C426234:TEL-ABL fusion protein, human; D000097764:ETS Translocation Variant 6 Protein; C108603:TEL-JAK2 fusion protein, human; D053614:Janus Kinase 2; C491568:TEL-JAK2 fusion protein, mouse; C494918:AKT1 protein, human