Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation.
Cahill, Mary R
AffiliationPaul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland;
Cell Transformation, Neoplastic
E2F1 Transcription Factor
Electrophoretic Mobility Shift Assay
Gene Expression Regulation, Neoplastic
Intracellular Signaling Peptides and Proteins
Leukemia, Myeloid, Acute
Mice, Inbred C57BL
MetadataShow full item record
CitationRegulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation. 2014, 123 (15):2389-400 Blood
AbstractThe loss of regulation of cell proliferation is a key event in leukemic transformation, and the oncogene tribbles (Trib)2 is emerging as a pivotal target of transcription factors in acute leukemias. Deregulation of the transcription factor E2F1, normally repressed by CCAAT enhancer-binding protein α (C/EBPα)-p42, occurs in acute myeloid leukemia (AML), resulting in the perturbation of cell cycle and apoptosis, emphasizing its importance in the molecular pathogenesis of AML. Here we show that E2F family members directly regulate Trib2 in leukemic cells and identify a feedback regulatory loop for E2F1, C/EBPα, and Trib2 in AML cell proliferation and survival. Further analyses revealed that E2F1-mediated Trib2 expression was repressed by C/EBPα-p42, and in normal granulocyte/macrophage progenitor cells, we detect C/EBPα bound to the Trib2 promoter. Pharmacological inhibition of the cell cycle or Trib2 knockdown resulted in a block in AML cell proliferation. Our work proposes a novel paradigm whereby E2F1 plays a key role in the regulation of Trib2 expression important for AML cell proliferation control. Importantly, we identify the contribution of dysregulated C/EBPα and E2F1 to elevated Trib2 expression and leukemic cell survival, which likely contributes to the initiation and maintenance of AML and may have significant implications for normal and malignant hematopoiesis.
- The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia.
- Authors: O'Connor C, Lohan F, Campos J, Ohlsson E, Salomè M, Forde C, Artschwager R, Liskamp RM, Cahill MR, Kiely PA, Porse B, Keeshan K
- Issue date: 2016 Oct 6
- Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia.
- Authors: Keeshan K, He Y, Wouters BJ, Shestova O, Xu L, Sai H, Rodriguez CG, Maillard I, Tobias JW, Valk P, Carroll M, Aster JC, Delwel R, Pear WS
- Issue date: 2006 Nov
- Inverse and correlative relationships between TRIBBLES genes indicate non-redundant functions during normal and malignant hemopoiesis.
- Authors: Salomé M, Hopcroft L, Keeshan K
- Issue date: 2018 Oct
- Differential ability of Tribbles family members to promote degradation of C/EBPalpha and induce acute myelogenous leukemia.
- Authors: Dedhia PH, Keeshan K, Uljon S, Xu L, Vega ME, Shestova O, Zaks-Zilberman M, Romany C, Blacklow SC, Pear WS
- Issue date: 2010 Aug 26
- Trib2 Suppresses Tumor Initiation in Notch-Driven T-ALL.
- Authors: Stein SJ, Mack EA, Rome KS, Pajcini KV, Ohtani T, Xu L, Li Y, Meijerink JP, Faryabi RB, Pear WS
- Issue date: 2016