A Trib2-p38 axis controls myeloid leukaemia cell cycle and stress response signalling

Salomé, M. , Magee, A., Yalla, K., Chaudhury, S. , Sarrou, E. , Carmody, R. J. and Keeshan, K. (2018) A Trib2-p38 axis controls myeloid leukaemia cell cycle and stress response signalling. Cell Death and Disease, 9(5), 443. (doi:10.1038/s41419-018-0467-3) (PMID:29670085) (PMCID:PMC5906628)

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Abstract

Trib2 pseudokinase is involved in the etiology of a number of cancers including leukaemia, melanoma, ovarian, lung and liver cancer. Both high and low Trib2 expression levels correlate with different types of cancer. Elevated Trib2 expression has oncogenic properties in both leukaemia and lung cancer dependent on interactions with proteasome machinery proteins and degradation of transcription factors. Here, we demonstrated that Trib2 deficiency conferred a growth and survival advantage both at steady state and in stress conditions in leukaemia cells. In response to stress, wild type leukaemia cells exited the cell cycle and underwent apoptosis. In contrast, Trib2 deficient leukaemia cells continued to enter mitosis and survive. We showed that Trib2 deficient leukaemia cells had defective MAPK p38 signalling, which associated with a reduced γ-H2Ax and Chk1 stress signalling response, and continued proliferation following stress, associated with inefficient activation of cell cycle inhibitors p21, p16 and p19. Furthermore, Trib2 deficient leukaemia cells were more resistant to chemotherapy than wild type leukaemia cells, having less apoptosis and continued propagation. Trib2 re-expression or pharmacological activation of p38 in Trib2 deficient leukaemia cells sensitised the cells to chemotherapy-induced apoptosis comparable with wild type leukaemia cells. Our data provide evidence for a tumour suppressor role of Trib2 in myeloid leukaemia via activation of p38 stress signalling. This newly identified role indicates that Trib2 may counteract the propagation and chemotherapy resistance of leukaemia cells.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Chaudhury, Dr Shahzya and Sarrou, Evgenia and Salome, Ms Mara and Carmody, Dr Ruaidhri and Keeshan, Dr Karen and Yalla, Dr Krishna
Authors: Salomé, M., Magee, A., Yalla, K., Chaudhury, S., Sarrou, E., Carmody, R. J., and Keeshan, K.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Cell Death and Disease
Publisher:Nature Publishing Group
ISSN:2041-4889
ISSN (Online):2041-4889
Published Online:18 April 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Cell Death and Disease 9(5): 443
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 (CRUK)C596/A18076RI CANCER SCIENCES
623941Targeting Trib2 oncogenic signalling in normal and malignant stem cells.Karen KeeshanBloodwise (LRF)13011RI CANCER SCIENCES
671081Investigating NF-kB p50 phosphorylation and the regulation of transcriptionRuaidhri CarmodyMedical Research Council (MRC)MR/M010694/1III -IMMUNOLOGY
659831Dissecting the function of Bcl-3 in NF-kappaB signaling in B cellsRuaidhri CarmodyBiotechnology and Biological Sciences Research Council (BBSRC)BB/M003671/1RI INFECTION IMMUNITY & INFLAMMATION