TGF-β induces apoptosis in human B cells by transcriptional regulation of BIK and BCL-XL
Open Access
- 9 January 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 16 (4), 593-602
- https://doi.org/10.1038/cdd.2008.183
Abstract
Transforming growth factor-β (TGF-β) potently induces apoptosis in Burkitt's lymphoma (BL) cell lines and in explanted primary human B lymphocytes. The physiological relevance and mechanism of TGF-β-mediated apoptosis induction in these cells remains to be determined. Here we demonstrate the requirement for TGF-β-mediated regulation of BIK and BCL-XL to activate an intrinsic apoptotic pathway in centroblastic BL cells. TGF-β directly induced transcription of BIK and a consensus Smad-binding element identified in the BIK promoter recruits TGF-β-activated Smad transcription factor complexes in vivo. TGF-β also transcriptionally repressed expression of the apoptosis inhibitor BCL-XL. Inhibition of BCL-XL sensitised BL cells to TGF-β-induced apoptosis whereas overexpression of BCL-XL or suppression of BIK by shRNA, diminished TGF-β-induced apoptosis. BIK and BCL-XL were also identified as TGF-β target genes in purified normal human centroblast B cells and immunohistochemical analyses of tonsil tissue revealed widespread TGF-β receptor-regulated Smad activation and a focal pattern of BIK expression. Furthermore, using a selective inhibitor of the TGF-β receptor we provide evidence that autocrine TGF-β signalling through ALK5 contributes to the default apoptotic programme in normal human centroblasts undergoing spontaneous apoptosis. Our data suggests that TGF-β may act as a physiological mediator of human germinal centre homoeostasis by regulation of BIK and BCL-XL.Keywords
This publication has 40 references indexed in Scilit:
- NBK/BIK antagonizes MCL-1 and BCL-XL and activates BAK-mediated apoptosis in response to protein synthesis inhibitionGenes & Development, 2007
- Transcriptional activation of the proapoptotic bik gene by E2F proteins in cancer cellsFEBS Letters, 2006
- Role of transforming growth factor-β in hematologic malignanciesBlood, 2006
- TRANSFORMING GROWTH FACTOR-β REGULATION OF IMMUNE RESPONSESAnnual Review of Immunology, 2006
- Probing tumor phenotypes using stable and regulated synthetic microRNA precursorsNature Genetics, 2005
- Repression of Runx2 function by TGF-β through recruitment of class II histone deacetylases by Smad3The EMBO Journal, 2005
- Transcriptional cross-regulation of RUNX1 by RUNX3 in human B cellsOncogene, 2005
- Proapoptotic BH3-Only Bcl-2 Family Member Bik/Blk/Nbk Is Expressed in Hemopoietic and Endothelial Cells but Is Redundant for Their Programmed DeathMolecular and Cellular Biology, 2004
- Relaxed Negative Selection in Germinal Centers and Impaired Affinity Maturation in bcl-xL Transgenic MiceThe Journal of Experimental Medicine, 1999
- Factors modifying survival pathways of germinal center B cells. Glucocorticoids and transforming growth factor‐β, but not cyclosporin A or anti‐CD19, block surface immunoglobulin‐mediated rescue from apoptosisEuropean Journal of Immunology, 1992