TGF-beta induces apoptosis in human B cells by transcriptional regulation of BIK and BCL-X-L

L. C. Spender (Lead / Corresponding author), D. I. O'Brien, D. Simpson, D. Dutt, C. D. Gregory, M. J. Allday, L. J. Clark, G. J. Inman (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    43 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)593-602
    Number of pages10
    JournalCell Death & Differentiation
    Volume16
    Issue number4
    DOIs
    Publication statusPublished - Apr 2009

    Keywords

    • 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

    Cite this

    Spender, L. C. ; O'Brien, D. I. ; Simpson, D. ; Dutt, D. ; Gregory, C. D. ; Allday, M. J. ; Clark, L. J. ; Inman, G. J. / TGF-beta induces apoptosis in human B cells by transcriptional regulation of BIK and BCL-X-L. In: Cell Death & Differentiation. 2009 ; Vol. 16, No. 4. pp. 593-602.
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    abstract = "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.",
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    TGF-beta induces apoptosis in human B cells by transcriptional regulation of BIK and BCL-X-L. / Spender, L. C. (Lead / Corresponding author); O'Brien, D. I.; Simpson, D.; Dutt, D.; Gregory, C. D.; Allday, M. J.; Clark, L. J.; Inman, G. J. (Lead / Corresponding author).

    In: Cell Death & Differentiation, Vol. 16, No. 4, 04.2009, p. 593-602.

    Research output: Contribution to journalArticle

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