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

被引：71
作者：
Spender, L. C. [1 ]
O'Brien, D. I. [1 ]
Simpson, D. [2 ]
Dutt, D. [1 ]
Gregory, C. D. [3 ]
Allday, M. J. [4 ]
Clark, L. J. [5 ]
Inman, G. J. [1 ]
机构：
[1] Beatson Inst Canc Res, Growth Factor Signalling Lab, Glasgow G61 1BD, Lanark, Scotland
[2] Stobhill Gen Hosp, Dept Otolaryngol, Glasgow G21 3UW, Lanark, Scotland
[3] Univ Edinburgh, Queens Med Res Inst, MRC, Ctr Inflammat Res, Edinburgh EH16 4TJ, Midlothian, Scotland
[4] Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Virol, London W2 1PG, England
[5] So Gen Hosp, Dept Otolaryngol, Glasgow G51 4TF, Lanark, Scotland
来源：
CELL DEATH AND DIFFERENTIATION | 2009年 / 16卷 / 04期
关键词：
TGF-beta; apoptosis; centroblast; BIK; BCL-X-L; GROWTH-FACTOR-BETA; GERMINAL-CENTER REACTION; BURKITTS-LYMPHOMA; MEDIATED APOPTOSIS; L EXPRESSION; DEATH; BCL-X(L); PROTEIN; GENE; DOMAIN;
D O I：
10.1038/cdd.2008.183
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Transforming growth factor-beta (TGF-beta) potently induces apoptosis in Burkitt's lymphoma (BL) cell lines and in explanted primary human B lymphocytes. The physiological relevance and mechanism of TGF-beta-mediated apoptosis induction in these cells remains to be determined. Here we demonstrate the requirement for TGF-beta-mediated regulation of BIK and BCL-X-L to activate an intrinsic apoptotic pathway in centroblastic BL cells. TGF-beta directly induced transcription of BIK and a consensus Smad-binding element identified in the BIK promoter recruits TGF-beta-activated Smad transcription factor complexes in vivo. TGF-beta also transcriptionally repressed expression of the apoptosis inhibitor BCL-X-L. Inhibition of BCL-X-L sensitised BL cells to TGF-beta-induced apoptosis whereas overexpression of BCL-X-L or suppression of BIK by shRNA, diminished TGF-beta-induced apoptosis. BIK and BCL-X-L were also identified as TGF-beta target genes in purified normal human centroblast B cells and immunohistochemical analyses of tonsil tissue revealed widespread TGF-beta receptor-regulated Smad activation and a focal pattern of BIK expression. Furthermore, using a selective inhibitor of the TGF-beta receptor we provide evidence that autocrine TGF-beta signalling through ALK5 contributes to the default apoptotic programme in normal human centroblasts undergoing spontaneous apoptosis. Our data suggests that TGF-beta may act as a physiological mediator of human germinal centre homoeostasis by regulation of BIK and BCL-X-L.
引用
收藏
页码：593 / 602
页数：10
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