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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.

SUBMITTER: Dedhia PH

PROVIDER: S-EPMC2938240 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Differential ability of Tribbles family members to promote degradation of C/EBPalpha and induce acute myelogenous leukemia.

Dedhia Priya H PH 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

Blood 20100421 8

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 struct ...[more]

PMID: 20410507

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Project description:BACKGROUND:Chemoresistance remains a significant challenge in chronic myelogenous leukemia (CML) management, which is one of the most critical prognostic factors. Elucidation the molecular mechanisms underlying the resistance to chemoresistance may lead to better clinical outcomes. RESULTS:In order to identify potential protein targets involved in the drug-resistant phenotype of leukemia, especially the chronic myelogenous leukemia (CML), we used a high-resolution "ultra-zoom" 2DE-based proteomics approach to characterize global protein expression patterns in doxorubicin-resistant myelogenous leukemia cells compared with parental control cells. Ultra-high resolution of 2DE was achieved by using a series of slightly overlapping narrow-range IPG strips during isoelectric focusing (IEF) separation. A total number of 44 proteins with altered abundances were detected and identified by MALDI-TOF or LC-MS/MS. Among these proteins, enolase, aldolase, HSP70 and sorcin were up-regulated in doxorubicin-resistant myelogenous leukemia cell line, whereas HSP27 was down-regulated. Some of the results have been validated by Western blotting. Both enolase and aldolase were first reported to be involved in chemoresistance, suggesting that process of glycolysis in doxorubicin-resistant myelogenous leukemia cells was accelerated to some extent to provide more energy to survive chemical stress. Possible roles of most of the identified proteins in development of chemoresistance in myelogenous leukemia cells were fully discussed. The results presented here could provide clues to further study for elucidating the mechanisms underlying drug resistance in leukemia. CONCLUSIONS:As a whole, under the chemical stress, the doxorubicin-resistant myelogenous leukemia cells may employ various protective strategies to survive. These include: (i) pumping the cytotoxic drug out of the cells by P-glycoprotein, (ii) increased storage of fermentable fuel, (iii) sophisticated cellular protection by molecular chaperones, (iv) improved handling of intracellular calcium, (v) increased glucose utilization via increased rates of glycolysis. In the present study, proteomic analysis of leukemia cells and their drug resistant variants revealed multiple alterations in protein expression. Our results indicate that the development of drug resistance in doxorubicin-resistant myelogenous leukemia cells is a complex phenomenon undergoing several mechanisms.

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Differential ability of Tribbles family members to promote degradation of C/EBPalpha and induce acute myelogenous leukemia.

Publications

Differential ability of Tribbles family members to promote degradation of C/EBPalpha and induce acute myelogenous leukemia.

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