Abstract
The c-myb proto-oncogene product (c-Myb) regulates both the proliferation and apoptosis of hematopoietic cells by inducing the transcription of a group of target genes. However, the biologically relevant molecular mechanisms that regulate c-Myb activity remain unclear. Here we report that c-Myb protein is phosphorylated and degraded by Wnt-1 signal via the pathway involving TAK1 (TGF-beta-activated kinase), HIPK2 (homeodomain-interacting protein kinase 2), and NLK (Nemo-like kinase). Wnt-1 signal causes the nuclear entry of TAK1, which then activates HIPK2 and the mitogen-activated protein (MAP) kinase-like kinase NLK. NLK binds directly to c-Myb together with HIPK2, which results in the phosphorylation of c-Myb at multiple sites, followed by its ubiquitination and proteasome-dependent degradation. Furthermore, overexpression of NLK in M1 cells abrogates the ability of c-Myb to maintain the undifferentiated state of these cells. The down-regulation of Myb by Wnt-1 signal may play an important role in a variety of developmental steps.
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 / metabolism*
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Chloramphenicol O-Acetyltransferase / metabolism
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Down-Regulation
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Glutathione Transferase / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins
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Leukemia, Myeloid / metabolism
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MAP Kinase Kinase Kinases / antagonists & inhibitors
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism*
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Mice
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Mitogen-Activated Protein Kinases / metabolism*
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Mitogens
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Nuclear Proteins / metabolism
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Phosphorylation
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Precipitin Tests
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Protein Serine-Threonine Kinases / metabolism*
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Mas
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-myb / antagonists & inhibitors
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Proto-Oncogene Proteins c-myb / metabolism*
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RNA, Small Interfering / pharmacology
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Saccharomyces cerevisiae
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Signal Transduction*
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Two-Hybrid System Techniques
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Ubiquitin
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Wnt Proteins
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Wnt1 Protein
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Zebrafish Proteins*
Substances
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Carrier Proteins
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Intracellular Signaling Peptides and Proteins
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MAS1 protein, human
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Mitogens
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Nuclear Proteins
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Proto-Oncogene Mas
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-myb
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RNA, Small Interfering
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Ubiquitin
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WNT1 protein, human
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Wnt Proteins
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Wnt1 Protein
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Wnt1 protein, mouse
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Zebrafish Proteins
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Chloramphenicol O-Acetyltransferase
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Glutathione Transferase
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HIPK2 protein, human
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Hipk2 protein, mouse
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NLK protein, human
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7