Abstract
T-cell acute lymphoblastic leukemia 1 (TAL1), also known as stem cell leukemia (SCL), plays important roles in differentiation of hematopoietic and endothelial cells and is deregulated in a high percentage of T-cell acute lymphoblastic leukemia (T-ALL). In this report we show that the intracellular concentration of TAL1 is regulated by transforming growth factor beta (TGF-beta), which triggers its polyubiquitylation and degradation by the proteasome. This effect is mediated by AKT1, which phosphorylates TAL1 at threonine 90. Immunoprecipitation experiments showed that this event increases association of TAL1 with the E3 ubiquitin ligase CHIP. The E47 heterodimerization partner of TAL1 hinders this association. Our observations indicate that activation of the TGF-beta and phosphatidylinositol 3-kinase/AKT pathways might reverse overexpression of TAL1 in leukemic cells by inducing proteolysis of this important oncogene.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution
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Androstadienes / pharmacology
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Dimerization
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HeLa Cells / metabolism
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Humans
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Jurkat Cells / metabolism
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Leupeptins / pharmacology
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Neoplasm Proteins / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Phosphothreonine / metabolism
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Proteasome Endopeptidase Complex / metabolism*
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Proteasome Inhibitors
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Protein Interaction Mapping
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Protein Processing, Post-Translational*
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism*
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T-Cell Acute Lymphocytic Leukemia Protein 1
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TCF Transcription Factors / metabolism
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Transcription Factor 7-Like 1 Protein
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Transforming Growth Factor beta1 / physiology*
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Ubiquitin / metabolism*
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Ubiquitin-Protein Ligases / metabolism
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Wortmannin
Substances
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Androstadienes
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Basic Helix-Loop-Helix Transcription Factors
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Leupeptins
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Neoplasm Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Proteasome Inhibitors
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Proto-Oncogene Proteins
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T-Cell Acute Lymphocytic Leukemia Protein 1
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TCF Transcription Factors
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TCF7L1 protein, human
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Transcription Factor 7-Like 1 Protein
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Transforming Growth Factor beta1
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Ubiquitin
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Phosphothreonine
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TAL1 protein, human
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STUB1 protein, human
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Ubiquitin-Protein Ligases
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AKT1 protein, human
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Proto-Oncogene Proteins c-akt
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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Wortmannin