E2F1 positively regulates Trib2 pseudokinase expression and proliferation in acute leukaemia

Keeshan, K. , Hannon, M., Rishi, L., Hasemann, M., Frank, A.-K., Timoney, J., O'Connor, C., Cahill, M. and Porse, B. (2013) E2F1 positively regulates Trib2 pseudokinase expression and proliferation in acute leukaemia. Experimental Hematology, 41(8), S50. (doi:10.1016/j.exphem.2013.05.197)

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Abstract

Deregulation of the transcription factor E2F1 occurs in AML, and it has been shown to induce both cell cycle progression and apoptosis. In normal granulopoiesis, proliferation arrest and differentiation mediated by C/EBPalpha involves repression of E2F1 target genes. Elevated Trib2 expression has been linked with a subset of human AML and dysregulated C/EBPalpha. Using promoter assays, mutational analyses and chromatin immunoprecipitation experiments, we show that E2F1 (and E2F2, E2F3, but not E2F4 or E2F5) are bound directly to the DNA on site-specific regions on the Trib2 promoter in leukaemic cells. Trib2 expression is decreased following siRNA-mediated knockdown of E2F1, and in E2F1 knockout cells as compared to wild type cells. The reintroduction of E2F1 rescued Trib2 expression showing that E2F1 is regulating the expression of endogenous Trib2. Further analyses revealed that this activation of Trib2 by E2F1 is repressed by wild type C/EBPalpha consistent with C/EBPalpha having a negative regulatory role on E2F1, and in normal GMP cells we detect C/EBPalpha bound to the Trib2 promoter. Conversely there was synergistic activation upon coexpression of the oncogenic C/EBPalpha truncated mutant, and Trib2 expression levels were elevated in GMPs from preleukaemic mutant C/EBPalpha mice compared to wild type GMPs. Indeed a positive correlation between Trib2 and E2F1 expression in AML datasets support these findings. Finally, inhibition of the cell cycle pathway in leukaemia cells expressing high endogenous levels of Trib2 protein resulted in G1 arrest with a reduction in E2F1 levels and Trib2 protein levels. Our work indicates that the cell cycle regulator E2F1 plays a key role in the control of Trib2 expression important for the control of cell proliferation and may have important implications for normal and malignant haematopoiesis.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Keeshan, Dr Karen and O'Connor, Ms Caitriona
Authors: Keeshan, K., Hannon, M., Rishi, L., Hasemann, M., Frank, A.-K., Timoney, J., O'Connor, C., Cahill, M., and Porse, B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Experimental Hematology
Publisher:Elsevier
ISSN:0301-472X

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