Critical role of STAT5 activation in transformation mediated by ZNF198-FGFR1.
The 8p11 myeloproliferative syndrome is an aggressive disorder caused by FGFR1 fusion proteins resulting from a subset of acquired translocations that target chromosome band 8p11. These chimeric proteins have constitutive FGFR1 tyrosine kinase activity and are believed to deregulate hemopoietic development in a manner analogous to BCR-ABL in chronic myeloid leukemia. Here we have studied the role of STAT proteins in transformation mediated by the most common of these fusions, ZNF198-FGFR1. We found that STATs 1, 3, and 5 were activated constitutively in ZNF198-FGFR1-transformed Ba/F3 cells and that STATs 2, 4, and 6 were also tyrosine-phosphorylated. Induction of dominant negative STAT mutants showed that activation of STAT5, but not STATs 1 or 3, was essential for the anti-apoptotic effect of ZNF198-FGFR1 and that STAT5 activation is essential for the elevated levels of BclXL in transformed cells. STAT5 activation was also shown to be required for continued cell cycle progression of BaF3/ZNF198-FGFR1 cells in conditions of cytokine deprivation and for up-regulation of the DNA repair protein Rad51. These findings suggest a critical role of STAT5 activation in transformation mediated by ZNF198-FGFR1.
Heath
Carol
C
Department of Haematology, Imperial College Faculty of Medicine, Hammersmith Hospital, W12 ONN London, UK.
Cross
Nicholas C P
NC
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic; D004247:DNA / Q000737:chemistry; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000378:metabolism; D005799:Genes, Dominant; D051379:Mice; D008894:Milk Proteins; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051135:Rad51 Recombinase; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014162:Transfection; D015854:Up-Regulation; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D015514:Oncogene Proteins, Fusion; D019253:Proto-Oncogene Proteins c-bcl-2; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C498438:Zmym2 protein, mouse; D051020:bcl-X Protein; D004247:DNA; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D016044:Fusion Proteins, bcr-abl; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse