Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation.

Hdl Handle:
http://hdl.handle.net/10147/322364
Title:
Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation.
Authors:
Rishi, Loveena; Hannon, Maura; Salomè, Mara; Hasemann, Marie; Frank, Anne-Katrine; Campos, Joana; Timoney, Jennifer; O'Connor, Caitriona; Cahill, Mary R; Porse, Bo; Keeshan, Karen
Affiliation:
Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland;
Citation:
Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation. 2014, 123 (15):2389-400 Blood
Journal:
Blood
Issue Date:
10-Apr-2014
URI:
http://hdl.handle.net/10147/322364
DOI:
10.1182/blood-2013-07-511683
PubMed ID:
24516045
Additional Links:
http://bloodjournal.hematologylibrary.org/content/123/15/2389.long?sso-checked=1
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.
Item Type:
Article
Language:
en
MeSH:
3T3 Cells; Animals; CCAAT-Enhancer-Binding Proteins; Cell Proliferation; Cell Transformation, Neoplastic; Chromatin Immunoprecipitation; E2F1 Transcription Factor; Electrophoretic Mobility Shift Assay; Feedback, Physiological; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Leukemia, Myeloid, Acute; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein-Serine-Threonine Kinases
ISSN:
1528-0020

Full metadata record

DC FieldValue Language
dc.contributor.authorRishi, Loveenaen_GB
dc.contributor.authorHannon, Mauraen_GB
dc.contributor.authorSalomè, Maraen_GB
dc.contributor.authorHasemann, Marieen_GB
dc.contributor.authorFrank, Anne-Katrineen_GB
dc.contributor.authorCampos, Joanaen_GB
dc.contributor.authorTimoney, Jenniferen_GB
dc.contributor.authorO'Connor, Caitrionaen_GB
dc.contributor.authorCahill, Mary Ren_GB
dc.contributor.authorPorse, Boen_GB
dc.contributor.authorKeeshan, Karenen_GB
dc.date.accessioned2014-07-03T13:54:57Z-
dc.date.available2014-07-03T13:54:57Z-
dc.date.issued2014-04-10-
dc.identifier.citationRegulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation. 2014, 123 (15):2389-400 Blooden_GB
dc.identifier.issn1528-0020-
dc.identifier.pmid24516045-
dc.identifier.doi10.1182/blood-2013-07-511683-
dc.identifier.urihttp://hdl.handle.net/10147/322364-
dc.description.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.en_GB
dc.language.isoenen
dc.relation.urlhttp://bloodjournal.hematologylibrary.org/content/123/15/2389.long?sso-checked=1en_GB
dc.rightsArchived with thanks to Blooden_GB
dc.subject.mesh3T3 Cells-
dc.subject.meshAnimals-
dc.subject.meshCCAAT-Enhancer-Binding Proteins-
dc.subject.meshCell Proliferation-
dc.subject.meshCell Transformation, Neoplastic-
dc.subject.meshChromatin Immunoprecipitation-
dc.subject.meshE2F1 Transcription Factor-
dc.subject.meshElectrophoretic Mobility Shift Assay-
dc.subject.meshFeedback, Physiological-
dc.subject.meshGene Expression Regulation, Neoplastic-
dc.subject.meshHumans-
dc.subject.meshIntracellular Signaling Peptides and Proteins-
dc.subject.meshLeukemia, Myeloid, Acute-
dc.subject.meshMice-
dc.subject.meshMice, Inbred C57BL-
dc.subject.meshMice, Knockout-
dc.subject.meshProtein-Serine-Threonine Kinases-
dc.titleRegulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation.en_GB
dc.typeArticleen
dc.contributor.departmentPaul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland;en_GB
dc.identifier.journalBlooden_GB
dc.description.fundingNo fundingen
dc.description.provinceMunsteren
dc.description.peer-reviewpeer-reviewen

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