Conditional knockdown of BCL2A1 reveals rate-limiting roles in BCR-dependent B-cell survival
- Author(s)
- Sochalska, M; Ottina, E; Tuzlak, S; Herzog, S; Herold, M; Villunger, A;
- Details
- Publication Year 2016-04-01,Volume 23,Issue #4,Page 628-639
- Journal Title
- Cell Death and Differentiation
- Publication Type
- Journal Article
- Abstract
- Bcl2 family proteins control mitochondrial apoptosis and its members exert critical cell type and differentiation stage-specific functions, acting as barriers against autoimmunity or transformation. Anti-apoptotic Bcl2a1/Bfl1/A1 is frequently deregulated in different types of blood cancers in humans but its physiological role is poorly understood as quadruplication of the Bcl2a1 gene locus in mice hampers conventional gene targeting strategies. Transgenic overexpression of A1, deletion of the A1-a paralogue or constitutive knockdown in the hematopoietic compartment of mice by RNAi suggested rate-limiting roles in lymphocyte development, granulopoiesis and mast cell activation. Here we report on the consequences of conditional knockdown of A1 protein expression using a reverse transactivator (rtTA)-driven approach that highlights a critical role for this Bcl2 family member in the maintenance of mature B-cell homeostasis. Furthermore, we define the A1/Bim (Bcl-2 interacting mediator of cell death) axis as a target of key kinases mediating B-cell receptor (BCR)-dependent survival signals, such as, spleen tyrosine kinase (Syk) and Brutons tyrosine kinase (Btk). As such, A1 represents a putative target for the treatment of B-cell-related pathologies depending on hyperactivation of BCR-emanating survival signals and loss of A1 expression accounts, in part, for the pro-apoptotic effects of Syk-or Btk inhibitors that rely on the 'BH3-only' protein Bim for cell killing.
- Publisher
- NPG
- Research Division(s)
- Molecular Genetics Of Cancer
- PubMed ID
- 26450454
- Publisher's Version
- https://doi.org/10.1038/cdd.2015.130
- Open Access at Publisher's Site
http://www.nature.com/cdd/journal/v23/n4/full/cdd2015130a.html- NHMRC Grants
- NHMRC/1049720,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2016-06-15 08:51:09
Last Modified: 2017-01-10 01:15:52