title: Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation.
abstract: The 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.
authors: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland;
authors: Loveena
authors: L
authors: Rishi
authors: Maura
authors: M
authors: Hannon
authors: Mara
authors: M
authors: Salomè
authors: Marie
authors: M
authors: Hasemann
authors: Anne-Katrine
authors: AK
authors: Frank
authors: Joana
authors: J
authors: Campos
authors: Jennifer
authors: J
authors: Timoney
authors: Caitriona
authors: C
authors: O'Connor
authors: Mary R
authors: MR
authors: Cahill
authors: Bo
authors: B
authors: Porse
authors: Karen
authors: K
authors: Keeshan
mesh_terms: D016475:3T3 Cells; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D050687:E2F1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D025461:Feedback, Physiological / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C515847:tribbles 2 protein, mouse; D017346:Protein Serine-Threonine Kinases