title: TRIB2 regulates normal and stress-induced thymocyte proliferation.
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.
authors.affiliation: Paul O'Gorman Leukemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
authors.forename: Kai Ling
authors.initials: KL
authors.lastname: Liang
authors.affiliation: Paul O'Gorman Leukemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow, UK.
authors.forename: Caitriona
authors.initials: C
authors.lastname: O'Connor
authors.affiliation: Paul O'Gorman Leukemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow, UK.
authors.forename: J Pedro
authors.initials: JP
authors.lastname: Veiga
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork , Cork, Ireland.
authors.forename: Tommie V
authors.initials: TV
authors.lastname: McCarthy
authors.affiliation: Paul O'Gorman Leukemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow, UK.
authors.forename: Karen
authors.identifier: 0000-0001-7266-0890
authors.initials: K
authors.lastname: Keeshan
keywords: cell cycle; genotoxic stress; oncogenic stress; proliferation; pseudokinase