An investigation of the role of TRIB2 in steady state and stressed haematopoiesis

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dc.contributor.advisorMcCarthy, Tommie V.en
dc.contributor.advisorKeeshan, Karenen
dc.contributor.authorLiang, Kai Ling
dc.contributor.funderHealth Research Boarden
dc.date.accessioned2016-09-21T10:45:18Z
dc.date.available2016-09-21T10:45:18Z
dc.date.issued2016
dc.date.submitted2016
dc.description.abstractTRIB2 is a member of the mammalian Tribbles family of serine/threonine pseudokinases (TRIB1-3). Here, we studied murine haematopoiesis after Trib2 ablation under steady state and proliferative stress conditions, including genotoxic and oncogenic stress. At the steady state, we found that TRIB2 loss did not adversely affect peripheral blood cell counts and populations. No detectable significant differences were found in the populations of haematopoietic stem and progenitor cells. However, Trib2-/- mice had significantly higher thymic cellularity due to the increased proliferation of Trib2-/- developing thymocytes which give rise to increased number of mature thymic subsets. During stressed haematopoiesis, Trib2-/- developing thymocytes demonstrate hypersensitivity to 5-fluorouracil-induced cell death. Nevertheless, Trib2-/- mice exhibit accelerated thymopoietic recovery post 5-fluorouracil treatment due to increased cell division kinetics of developing thymocytes. In an experimental murine T-cell acute lymphoblastic leukaemia (T-ALL) model, Trib2-/- mice had reduced latency in vivo which associated with aggressive T-ALL phenotypes and impaired activation of mitogen-activated protein kinase. Gene set enrichment analysis showed that TRIB2 expression is elevated in immature subtype of human T-ALL enriched with mitogen-activated protein kinase signalling. However, TRIB2 expression is suppressed in mature subtype of human T-ALL. Thus, TRIB2 emerges as a novel regulator of thymocyte cellular proliferation, important for the thymopoietic response to genotoxic and oncogenic stress, and possessing tumour suppressor function. In Drosophila, Tribbles promotes degradation of String which is an orthologue of mammalian CDC25 phosphatases in order to arrest cell cycle during embryonic development. Here, we showed that the role of Tribbles-induced degradation of String is evolutionarily conserved in TRIB2. We found that TRIB2 interacts with CDC25B/C but not CDC25A isoform. Overexpression of TRIB2 promotes polyubiquitination and degradation of CDC25C. Hence, future works are warranted to examine TRIB2-CDC25C interaction in the context of developing thymocytes and in T-cell acute lymphoblastic leukaemia, the malignant counterpart.en
dc.description.sponsorshipHealth Research Board (PhD Scholars Programme in Cancer Biology)en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationLiang, K. L. 2016. An investigation of the role of TRIB2 in steady state and stressed haematopoiesis. PhD Thesis, University College Cork.en
dc.identifier.endpage201en
dc.identifier.urihttps://hdl.handle.net/10468/3106
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2016, Kai Ling Liang.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectPseudokinaseen
dc.subjectTRIB2en
dc.subjectHaematopoiesisen
dc.subjectT-cell acute lymphoblastic leukaemiaen
dc.subjectThymopoiesisen
dc.subjectCellular proliferationen
dc.subjectCell division cycle 25 familyen
dc.thesis.opt-outfalse
dc.titleAn investigation of the role of TRIB2 in steady state and stressed haematopoiesisen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoral Degree (Structured)en
dc.type.qualificationnamePhD Scholars Programme in Cancer Biologyen
ucc.workflow.supervisort.mccarthy@ucc.ie
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