Abstract
Provirus insertion in the last intron of the Tpl-2 gene in retrovirus-induced rat T-cell lymphomas results in the enhanced expression of a carboxy-terminally truncated Tpl-2 kinase. Here we show that the truncated protein exhibits an approximately sevenfold higher catalytic activity and is two- to threefold more efficient in activating the MAPK and SAPK pathways relative to the wild-type protein. The truncated Tpl-2 protein and a GST fusion of the Tpl-2 carboxy-terminal tail interact when coexpressed in Sf9 cells. Their interaction down-regulates the kinase activity of the truncated protein suggesting that tail-directed intramolecular interactions regulate the Tpl-2 kinase. Tpl-2 transgenic mice expressing the wild-type protein from the proximal Lck promoter fail to show a biological phenotype, whereas mice expressing the truncated protein develop large-cell lymphoblastic lymphomas of T-cell origin. These results show that Tpl-2 is an oncogenic kinase that is activated by carboxy-terminal truncation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cell Line
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Enzyme Activation
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In Vitro Techniques
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Introns
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Lymphoma, T-Cell / enzymology
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Lymphoma, T-Cell / genetics
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Lymphoma, T-Cell / virology
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MAP Kinase Kinase Kinases*
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Mice
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Mice, Transgenic
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Molecular Sequence Data
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Moloney murine leukemia virus / genetics
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Peptide Fragments / genetics
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Protein Serine-Threonine Kinases / chemistry*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins / chemistry*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogenes
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Proviruses / genetics
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Rats
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Retroviridae Infections / enzymology
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Retroviridae Infections / genetics
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Retroviridae Infections / virology
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Tumor Virus Infections / enzymology
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Tumor Virus Infections / genetics
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Tumor Virus Infections / virology
Substances
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Peptide Fragments
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Proto-Oncogene Proteins
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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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MAP Kinase Kinase Kinases
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Map3k8 protein, mouse
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Map3k8 protein, rat