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Critical role of STAT5 activation in transformation mediated by ZNF198-FGFR1

Critical role of STAT5 activation in transformation mediated by ZNF198-FGFR1
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.
proto-oncogene proteins, leukemia, fibroblast growth factor, dna-binding proteins, non-U.S.gov't, tyrosine, fusion proteins, rad51 recombinase, protein-tyrosine kinase, milk, proto-oncogene proteins c-bcl-2, western, growth, proteins, precipitin tests, mutation, activity, protein, research support, oncogene proteins, plasmids, cell transformation, carrier proteins, milk proteins, role, apoptosis, chemistry, london, dna, animals, biosynthesis, dominant, genetics, trans-activators, syndrome, dna repair, transfection, blotting, fusion, receptors, receptor, phosphorylation, physiology, mice, neoplastic, cell cycle, type 1, bcl-x protein, signal transduction, recombinant fusion proteins, metabolism, flow cytometry, up-regulation, receptor protein-tyrosine kinases, stat5 transcription factor, cell separation, genes, cell line, bcr-abl
0021-9258
6666-6673
Heath, C.
0750b978-95cd-4551-8598-f8caf3cdafb3
Cross, N.C.
f87650da-b908-4a34-b31b-d62c5f186fe4
Heath, C.
0750b978-95cd-4551-8598-f8caf3cdafb3
Cross, N.C.
f87650da-b908-4a34-b31b-d62c5f186fe4

Heath, C. and Cross, N.C. (2004) Critical role of STAT5 activation in transformation mediated by ZNF198-FGFR1. The Journal of Biological Chemistry, 279 (8), 6666-6673. (doi:10.1074/jbc.M308743200).

Record type: Article

Abstract

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.

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More information

Published date: 2004
Keywords: proto-oncogene proteins, leukemia, fibroblast growth factor, dna-binding proteins, non-U.S.gov't, tyrosine, fusion proteins, rad51 recombinase, protein-tyrosine kinase, milk, proto-oncogene proteins c-bcl-2, western, growth, proteins, precipitin tests, mutation, activity, protein, research support, oncogene proteins, plasmids, cell transformation, carrier proteins, milk proteins, role, apoptosis, chemistry, london, dna, animals, biosynthesis, dominant, genetics, trans-activators, syndrome, dna repair, transfection, blotting, fusion, receptors, receptor, phosphorylation, physiology, mice, neoplastic, cell cycle, type 1, bcl-x protein, signal transduction, recombinant fusion proteins, metabolism, flow cytometry, up-regulation, receptor protein-tyrosine kinases, stat5 transcription factor, cell separation, genes, cell line, bcr-abl

Identifiers

Local EPrints ID: 59820
URI: http://eprints.soton.ac.uk/id/eprint/59820
ISSN: 0021-9258
PURE UUID: 6f8c728a-4408-4f71-a7c5-a04da2548e30
ORCID for N.C. Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 04 Sep 2008
Last modified: 16 Mar 2024 03:23

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Contributors

Author: C. Heath
Author: N.C. Cross ORCID iD

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