title: COP1 targets C/EBPα for degradation and induces acute myeloid leukemia via Trib1.
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.
authors.affiliation: Department of Tumor Cell Biology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yoshida
authors.forename: Jun-Ya
authors.initials: JY
authors.lastname: Kato
authors.forename: Ikuko
authors.initials: I
authors.lastname: Nakamae
authors.forename: Noriko
authors.initials: N
authors.lastname: Yoneda-Kato
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects; D000818:Animals; D016026:Bone Marrow Transplantation; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D009687:Nuclear Proteins; C523598:Trib1 protein, mouse; D016179:Granulocyte Colony-Stimulating Factor; C471982:COP1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases