Differential ability of Tribbles family members to promote degradation of C/EBPalpha and induce acute myelogenous leukemia.
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.
Dedhia
Priya H
PH
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Institute for Medicine & Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Keeshan
Karen
K
Uljon
Sacha
S
Xu
Lanwei
L
Vega
Maria E
ME
Shestova
Olga
O
Zaks-Zilberman
Meirav
M
Romany
Candice
C
Blacklow
Stephen C
SC
Pear
Warren S
WS
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
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
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