Abstract
Pim-1 is an oncogenic serine/threonine kinase implicated in cytokine-induced signal transduction and in development of lymphoid malignancies. However, its precise function as well as physiological substrates have remained unknown. In this study we demonstrate that Pim-1 can physically interact with the NFATc1 transcription factor and phosphorylate it in vitro on several serine residues. In contrast to previously recognized NFATc kinases, wild-type Pim-1 enhances NFATc-dependent transactivation and IL-2 production in Jurkat T cells, while kinase-deficient Pim-1 mutants inhibit them in a dominant negative fashion. Our results reveal a novel, phosphorylation-dependent regulatory mechanism targeting NFATc1 through which Pim-1 acts as a downstream effector of Ras to facilitate IL-2-dependent proliferation and/or survival of lymphoid cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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COS Cells
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / metabolism*
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Humans
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Interleukin-2 / biosynthesis
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Jurkat Cells
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Mutation
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NFATC Transcription Factors
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Nuclear Proteins*
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Phosphorylation
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Phosphoserine / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-pim-1
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Proto-Oncogene Proteins p21(ras) / metabolism
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Signal Transduction
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T-Lymphocytes / enzymology
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T-Lymphocytes / immunology*
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Transcription Factors / chemistry
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Transcription Factors / metabolism*
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Transcriptional Activation*
Substances
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DNA-Binding Proteins
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Interleukin-2
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NFATC Transcription Factors
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NFATC1 protein, human
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Nuclear Proteins
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Proto-Oncogene Proteins
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Transcription Factors
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Phosphoserine
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PIM1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-pim-1
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HRAS protein, human
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Proto-Oncogene Proteins p21(ras)