TGF-beta induces degradation of TAL1/SCL by the ubiquitin-proteasome pathway through AKT-mediated phosphorylation.
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.
Terme
Jean-Michel
JM
Laboratoire de Biologie Moléculaire de la Cellule, Unité Mixte de Recherche 5239, Centre National de la Recherche Scientifique, Ecole Normale Supérieure de Lyon, Institut Fédératif de Recherche 128 Biosciences Lyon Gerland, Lyon, France.
Lhermitte
Ludovic
L
Asnafi
Vahid
V
Jalinot
Pierre
P
D019943:Amino Acid Substitution; D000730:Androstadienes / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D019281:Dimerization; D006367:HeLa Cells / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D051820:TCF Transcription Factors / Q000378:metabolism; D058125:Transcription Factor 7-Like 1 Protein; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D051792:Basic Helix-Loop-Helix Proteins; D007976:Leupeptins; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010769:Phosphothreonine; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D053773:Transforming Growth Factor beta1; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000077191:Wortmannin; C544912:TCF7L1 protein, human; C067143:TAL1 protein, human; C467728:STUB1 protein, human; C494918:AKT1 protein, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde