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 language | English |
|---|---|
| Pages (from-to) | 593-602 |
| Number of pages | 10 |
| Journal | Cell Death & Differentiation |
| Volume | 16 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 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