title: Differential ability of Tribbles family members to promote degradation of C/EBPalpha and induce acute myelogenous leukemia.
abstract: Trib1, Trib2, and Trib3 are mammalian homologs of Tribbles, an evolutionarily conserved Drosophila protein family that mediates protein degradation. Tribbles proteins function as adapters to recruit E3 ubiquitin ligases and enhance ubiquitylation of the target protein to promote its degradation. Increased Trib1 and Trib2 mRNA expression occurs in human myeloid leukemia and induces acute myeloid leukemia in mice, whereas Trib3 has not been associated with leukemia. Given the high degree of structural conservation among Tribbles family members, we directly compared the 3 mammalian Tribbles in hematopoietic cells by reconstituting mice with hematopoietic stem cells retrovirally expressing these proteins. All mice receiving Trib1 or Trib2 transduced hematopoietic stem cells developed acute myeloid leukemia, whereas Trib3 mice did not. Our previous data indicated that Trib2-mediated degradation of the transcription factor, CCAAT/enhancer-binding protein-alpha (C/EBPalpha), is important for leukemogenesis. Similar to Trib2, Trib1 induced C/EBPalpha degradation and inhibited its function. In contrast, Trib3 failed to inactivate or promote efficient degradation of C/EBPalpha. These data reveal that the 3 Tribbles homologs differ in their ability to promote degradation of C/EBPalpha, which account for their differential ability to induce leukemia.
authors.affiliation: Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Institute for Medicine & Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Priya H
authors.initials: PH
authors.lastname: Dedhia
authors.forename: Karen
authors.initials: K
authors.lastname: Keeshan
authors.forename: Sacha
authors.initials: S
authors.lastname: Uljon
authors.forename: Lanwei
authors.initials: L
authors.lastname: Xu
authors.forename: Maria E
authors.initials: ME
authors.lastname: Vega
authors.forename: Olga
authors.initials: O
authors.lastname: Shestova
authors.forename: Meirav
authors.initials: M
authors.lastname: Zaks-Zilberman
authors.forename: Candice
authors.initials: C
authors.lastname: Romany
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Blacklow
authors.forename: Warren S
authors.initials: WS
authors.lastname: Pear
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C523598:Trib1 protein, mouse; C515847:tribbles 2 protein, mouse; D017346:Protein Serine-Threonine Kinases
references.citation: Blood. 2002 Apr 15;99(8):2776-85
references.pmid: 11929766
references.citation: Cell. 2000 May 26;101(5):511-22
references.pmid: 10850493
references.citation: Science. 2003 Jun 6;300(5625):1574-7
references.pmid: 12791994
references.citation: J Clin Invest. 2006 Sep;116(9):2464-72
references.pmid: 16906224
references.citation: Cancer Genet Cytogenet. 2007 Jul 1;176(1):58-60
references.pmid: 17574965
references.citation: J Clin Oncol. 2006 Aug 20;24(24):3887-94
references.pmid: 16864856
references.citation: Cancer Cell. 2006 Nov;10(5):401-11
references.pmid: 17097562
references.citation: Oncogene. 2003 May 8;22(18):2823-35
references.pmid: 12743605
references.citation: J Biol Chem. 2006 Oct 6;281(40):29719-29
references.pmid: 16887816
references.citation: J Biol Chem. 2004 Oct 8;279(41):42703-8
references.pmid: 15299019
references.citation: Nat Protoc. 2007;2(4):924-32
references.pmid: 17446874
references.citation: Immunity. 1999 Sep;11(3):299-308
references.pmid: 10514008
references.citation: Curr Biol. 2000 Jun 1;10(11):623-9
references.pmid: 10837248
references.citation: Immunol Lett. 2006 Apr 15;104(1-2):171-7
references.pmid: 16364454
references.citation: Blood. 2007 May 1;109(9):3998-4005
references.pmid: 17227832
references.citation: Science. 2006 Jun 23;312(5781):1763-6
references.pmid: 16794074
references.citation: Blood. 1999 Jul 15;94(2):560-71
references.pmid: 10397723
references.citation: J Immunol. 1987 Jun 1;138(11):3829-35
references.pmid: 2438328
references.citation: J Biol Chem. 2007 Aug 17;282(33):24075-82
references.pmid: 17576771
references.citation: Mol Cell Biol. 2000 Oct;20(20):7505-15
references.pmid: 11003647
references.citation: Exp Cell Res. 2008 Apr 15;314(7):1566-74
references.pmid: 18316073
references.citation: J Exp Med. 2007 Sep 3;204(9):2233-9
references.pmid: 17724128
references.citation: J Clin Invest. 2008 Sep;118(9):3181-94
references.pmid: 18677410
references.citation: Biochem Biophys Res Commun. 2007 Feb 23;353(4):933-8
references.pmid: 17207467
references.citation: Cell. 2000 May 26;101(5):523-31
references.pmid: 10850494
references.citation: J Biol Chem. 2006 Apr 21;281(16):11126-34
references.pmid: 16452480
references.citation: Mol Cell. 2000 Jul;6(1):23-30
references.pmid: 10949024
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4465-70
references.pmid: 11904358
references.citation: Hum Mol Genet. 2006 Mar 15;15(6):933-42
references.pmid: 16452126