Loss of Bak enhances lymphocytosis but does not ameliorate thrombocytopaenia in BCL-2 transgenic mice

Vandenberg, CJ; Josefsson, EC; Campbell, KJ; James, C; Lawlor, KE; Kile, BT; Cory, S

Author(s): Vandenberg, CJ; Josefsson, EC; Campbell, KJ; James, C; Lawlor, KE; Kile, BT; Cory, S;
Details: Publication Year 2014-01-24,Volume 21,Issue #5,Page 676-84
Journal Title: Cell death and differentiation
Publication Type: Journal Article
Abstract: Bax and Bak are critical effectors of apoptosis. Although both are widely expressed and usually functionally redundant, recent studies suggest that Bak has particular importance in certain cell types. Genetic and biochemical studies indicate that Bak activation is prevented primarily by Mcl-1 and Bcl-xL, whereas Bax is held in check by all pro-survival Bcl-2 homologues, including Bcl-2 itself. In this study, we have investigated whether loss of Bak or elevated Mcl-1 modulates haemopoietic abnormalities provoked by overexpression of Bcl-2. The Mcl-1 transgene had little impact, probably because the expression level was insufficient to effectively reduce Bak activation. However, loss of Bak enhanced lymphocytosis in vavP-BCL-2 transgenic mice and increased resistance of their thymocytes to some cytotoxic agents, implying that Bak-specific signals can be triggered in certain lymphoid populations. Nevertheless, lack of Bak had no significant impact on thymic abnormalities in vavP-BCL-2tg mice, which kinetic analysis suggested was due to accumulation of self-reactive thymocytes that resist deletion. Intriguingly, although Bak-/- mice have elevated platelet counts, Bak-/-vavP-BCL-2 mice, like vavP-BCL-2 littermates, were thrombocytopaenic. To clarify why, the vavP-BCL-2 platelet phenotype was scrutinised more closely. Platelet life span was found to be elevated in vavP-BCL-2 mice, which should have provoked thrombocytosis, as in Bak-/- mice. Analysis of bone marrow chimaeric mice suggested the low platelet phenotype was due principally to extrinsic factors. Following splenectomy, blood platelets remained lower in vavP-BCL-2 than wild-type mice. However, in Rag1-/- BCL-2tg mice, platelet levels were normal, implying that elevated lymphocytes are primarily responsible for BCL-2tg-induced thrombocytopaenia.Cell Death and Differentiation advance online publication, 24 January 2014; doi:10.1038/cdd.2013.201.
Publisher: NPG
Keywords: Bcl-2; Mcl-1; Bak; apoptosis; thrombocytopaenia; haemopoiesis
Research Division(s): Molecular Genetics Of Cancer; Cancer And Haematology; Inflammation; Chemical Biology
Publisher's Version: https://doi.org/10.1038/cdd.2013.201
Open Access at Publisher's Site: http://www.nature.com/cdd/journal/vaop/ncurrent/full/cdd2013201a.html
Terms of Use/Rights Notice: This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/.

Creation Date: 2014-03-04 10:12:24