Abstract
Signal transducer and activator of transcription 5 (STAT5) plays a critical role in cytokine-induced survival of hematopoietic cells. One of the STAT5 target genes is pim-1, which encodes an oncogenic serine/threonine kinase. Here we demonstrate that Pim-1 inhibits STAT5-dependent transcription in cells responsive to interleukin-3, prolactin, or erythropoietin. Ectopic expression of Pim-1 in cytokine-dependent FDCP1 myeloid cells results in reduced tyrosine phosphorylation and DNA binding of STAT5, indicating that Pim-1 interferes already with the initial steps of STAT5 activation. However, the Pim-1 kinase does not directly phosphorylate or bind to STAT5. By contrast, Pim-1 interacts with suppressor of cytokine signaling 1 (SOCS1) and SOCS3 and potentiates their inhibitory effects on STAT5, most likely via phosphorylation-mediated stabilization of the SOCS proteins. Thus, both Pim and SOCS family proteins may be components of a negative feedback mechanism that allows STAT5 to attenuate its own activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / physiology
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Feedback, Physiological
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Mice
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Milk Proteins*
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Myeloid Cells / cytology
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Myeloid Cells / metabolism
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Phosphorylation
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Protein Binding
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Serine-Threonine Kinases / physiology*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-pim-1
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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STAT5 Transcription Factor
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators / antagonists & inhibitors*
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Trans-Activators / physiology
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic*
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Transfection
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Milk Proteins
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Proto-Oncogene Proteins
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Repressor Proteins
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STAT5 Transcription Factor
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Socs1 protein, mouse
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Socs3 protein, mouse
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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Transcription Factors
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Pim1 protein, mouse
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-pim-1