Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 278, Issue 20, Pages 18069-18077Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M211958200
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- NCI NIH HHS [CA55536, CA80095] Funding Source: Medline
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Transforming growth factor-beta (TGFbeta) is a potent growth inhibitor and inducer of apoptosis in B lymphocytes and is essential for immune regulation and maintenance of self-tolerance. Here we show that exogenous overexpression of Smad3 potentiates TGFbeta-induced apoptosis and expression of the pro-apoptotic protein Bim in WEHI 231 B lymphocytes. Overexpression of dominant-negative forms of Smad3 abrogate these TGFbeta-induced responses. We also demonstrate that TGFbeta induces Bim protein expression concomitant with its induction of apoptosis in the mouse progenitor B lymphocyte cell line, Ba/F3. Enhanced expression of Bim protein induced by TGFbeta is associated with an increased association of Bim with Bcl-2 and a concomitant loss of mitochondrial membrane potential. Furthermore, we find that the anti-apoptotic effect of the pro-survival cytokine CD40 results in the abrogation of TGFbeta-mediated Bim induction. Our data provide the first evidence of Bim expression levels that are increased by the addition of a pro-apoptotic cytokine, TGFbeta, and also suggest that the TGFbeta-specific transcription factor Smad3 plays a role in mediating Bim expression levels and apoptosis.
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