期刊
CELL DISCOVERY
卷 2, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/celldisc.2015.50
关键词
cell cycle; genotoxic stress; oncogenic stress; proliferation; pseudokinase
类别
资金
- Cancer Research UK Glasgow Centre [C596/A18076]
- Biological Service Unit facilities at the Cancer Research UK Beatson Institute [C596/A17196]
- Kay Kendall foundation [KKL501]
- Howat foundation
- Children with Cancer UK
- Health Research Board Ireland
- Children's Leukemia Research Project
- Leukaemia & Lymphoma Research Project [13011]
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, Trib(2-/-) 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, Trib(2-/-) 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.
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