TRIB2 regulates normal and stress-induced thymocyte proliferation

Liang, K. L., O'Connor, C., Veiga, J. P., McCarthy, T. V. and Keeshan, K. (2016) TRIB2 regulates normal and stress-induced thymocyte proliferation. Cell Discovery, 2, 15050. (doi:10.1038/celldisc.2015.50) (PMID:27462446) (PMCID:PMC4860960)

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Abstract

TRIB2, a serine/threonine pseudokinase identified as an oncogene, is expressed at high levels in the T-cell compartment of hematopoiesis. The proliferation of developing thymocytes is tightly controlled to prevent leukemic transformation of T cells. Here we examine Trib2 loss in murine hematopoiesis under steady state and proliferative stress conditions, including genotoxic and oncogenic stress. Trib2−/− developing thymocytes show increased proliferation, and Trib2−/− mice have significantly higher thymic cellularity at steady state. During stress hematopoiesis, Trib2−/− developing thymocytes undergo accelerated proliferation and demonstrate hypersensitivity to 5-fluorouracil (5-FU)-induced cell death. Despite the increased cell death post 5-FU-induced proliferative stress, Trib2−/− mice exhibit accelerated thymopoietic recovery post treatment due to increased cell division kinetics of developing thymocytes. The increased proliferation in Trib2−/− thymocytes was exacerbated under oncogenic stress. In an experimental murine T-cell acute lymphoblastic leukemia (T-ALL) model, Trib2−/− mice had reduced latency in vivo, which associated with impaired MAP kinase (MAPK) activation. High and low expression levels of Trib2 correlate with immature and mature subtypes of human T-ALL, respectively, and associate with MAPK. Thus, TRIB2 emerges as a novel regulator of thymocyte cellular proliferation, important for the thymopoietic response to genotoxic and oncogenic stress, and possessing tumor suppressor function

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Keeshan, Dr Karen and Veiga, Dr Joaquim Pedro and O'Connor, Ms Caitriona
Authors: Liang, K. L., O'Connor, C., Veiga, J. P., McCarthy, T. V., and Keeshan, K.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Discovery
Publisher:Nature Publishing Group
ISSN:2056-5968
ISSN (Online):2056-5968
Published Online:25 March 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Cell Discovery 2:15050
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
647981CR-UK Centre renewalKaren VousdenCancer Research UK (CAN-RES-UK)C596/A18076RI CANCER SCIENCES
623941Targeting Trib2 oncogenic signalling in normal and malignant stem cells.Karen KeeshanBloodwise (BLOODWIS)13011RI CANCER SCIENCES