Differential ability of Tribbles family members to promote degradation of C/EBPα 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/EBP alpha), is important for leukemogenesis. Similar to Trib2, Trib1 induced C/EBP alpha degradation and inhibited its function. In contrast, Trib3 failed to inactivate or promote efficient degradation of C/EBP alpha. These data reveal that the 3 Tribbles homologs differ in their ability to promote degradation of C/EBP alpha, which account for their differential ability to induce leukemia. (Blood. 2010; 116(8): 1321-1328)