TGF-β induces apoptosis in human B cells by transcriptional regulation of BIK and BCL-XL

Spender, L.C., O'Brien, D.I., Simpson, D., Dutt, D., Gregory, C.D., Allday, M.J., Clark, L.J. and Inman, G.J. (2009) TGF-β induces apoptosis in human B cells by transcriptional regulation of BIK and BCL-XL. Cell Death and Differentiation, 16(4), pp. 593-602. (doi: 10.1038/cdd.2008.183) (PMID:19136942) (PMCID:PMC2857326)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Inman, Professor Gareth
Authors: Spender, L.C., O'Brien, D.I., Simpson, D., Dutt, D., Gregory, C.D., Allday, M.J., Clark, L.J., and Inman, G.J.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cell Death and Differentiation
Publisher:Springer Nature
ISSN:1350-9047
ISSN (Online):1476-5403

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