Abstract
Constitutive activation of the JAK-STAT pathway is frequent in cancer and contributes to oncogenesis. Here, we took advantage of the Ba/F3 cell line, a murine proB cell line dependent on IL-3 for growth, to analyse mechanisms of constitutive STAT activation in vitro. Cytokine-independent and tumorigenic Ba/F3 cell lines were derived from a two-step selection process. Cells transfected with a defective IL-9 receptor acquire IL-9 responsiveness during a first step of selection, and progress after a second selection step to autonomously growing tumorigenic cells. Microarray analysis pointed to JAK1 overexpression as a key genetic event in this transformation. Overexpression of JAK1 not only increased the sensitivity to IL-9 but also allowed a second selection step toward cytokine-independent growth with constitutive STAT activation. This progression was dependent on a functional FERM and kinase JAK1 domain. Similar results were observed after JAK2, JAK3 and TYK2 overexpression. All autonomous cell lines showed an activation of STAT5, ERK1-2 and AKT but only TYK2-overexpressing cell lines showed a constitutive activation of STAT3. Thus, JAK overexpression can be considered as one of the oncogenic events leading to the constitutive activation of the JAK-STAT pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Cell Proliferation*
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Cell Survival
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Cell Transformation, Neoplastic / metabolism*
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Gene Expression Profiling
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Gene Expression Regulation
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Humans
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Interleukin-9 / pharmacology
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Janus Kinase 1 / genetics
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Janus Kinase 1 / metabolism
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Janus Kinase 2 / genetics
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Janus Kinase 2 / metabolism
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Janus Kinase 3 / genetics
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Janus Kinase 3 / metabolism
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Janus Kinases / genetics
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Janus Kinases / metabolism*
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Mice
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Oligonucleotide Array Sequence Analysis
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Precursor Cells, B-Lymphoid / metabolism
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Precursor Cells, B-Lymphoid / pathology*
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Interleukin-9 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism*
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STAT5 Transcription Factor / metabolism
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Signal Transduction*
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TYK2 Kinase / genetics
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TYK2 Kinase / metabolism
Substances
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Interleukin-9
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Receptors, Interleukin-9
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STAT3 Transcription Factor
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STAT5 Transcription Factor
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JAK3 protein, human
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Jak1 protein, mouse
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Jak2 protein, mouse
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Janus Kinase 1
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Janus Kinase 2
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Janus Kinase 3
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Janus Kinases
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TYK2 Kinase
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TYK2 protein, human
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3