Abstract
The ubiquitin ligase constitutively photomorphogenic 1 (COP1) is involved in many biological responses in mammalian cells, but its role in tumorigenesis remains unclear. Here we show that COP1 is a ubiquitin ligase for the tumor suppressor CCAAT/enhancer-binding protein (C/EBPα) and promotes its degradation in vivo, thereby blocking myeloid differentiation of hematopoietic cells for tumorigenesis. In this process, mammalian homolog of Tribbles, Trib1, which contains a COP1-binding motif, is essential for down-regulation of C/EBPα expression. Murine bone marrow transplantation experiments showed that coexpression of COP1 accelerates development of acute myeloid leukemia induced by Trib1, which pathologically resembles that of p42C/EBPα-deficient mice. Interestingly, coexpression of ligase activity-deficient COP1 mutant abrogated Trib1-induced leukemogenesis. These results indicate that COP1 and Trib1 act as an oncoprotein complex functioning upstream of C/EBPα, and its ligase activity is crucial for leukemogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alternative Splicing / drug effects
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Animals
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Bone Marrow Transplantation
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CCAAT-Enhancer-Binding Protein-alpha / metabolism*
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Cell Differentiation / drug effects
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Granulocyte Colony-Stimulating Factor / pharmacology
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Granulocytes / drug effects
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Granulocytes / metabolism
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Granulocytes / pathology
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HEK293 Cells
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Humans
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Intracellular Signaling Peptides and Proteins / metabolism*
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Leukemia, Myeloid, Acute / metabolism*
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Leukemia, Myeloid, Acute / pathology*
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Mice
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Mice, Inbred C57BL
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Mutant Proteins / metabolism
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Mutation / genetics
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NIH 3T3 Cells
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Nuclear Proteins / metabolism*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Proteolysis* / drug effects
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Ubiquitin-Protein Ligases / metabolism*
Substances
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CCAAT-Enhancer-Binding Protein-alpha
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Intracellular Signaling Peptides and Proteins
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Mutant Proteins
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Nuclear Proteins
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Trib1 protein, mouse
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Granulocyte Colony-Stimulating Factor
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COP1 protein, mouse
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Ubiquitin-Protein Ligases
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Protein Serine-Threonine Kinases