Transforming growth factor beta (TGFbeta)-induced apoptosis: the rise & fall of Bim.

Transforming growth factor beta (TGFbeta) regulates essential cellular functions such as cellular proliferation, differentiation and apoptosis. Multiple apoptotic mediators and signaling pathways have been implicated in TGFbeta-induced apoptosis. Bim, a BH3-only protein, is critical for apoptosis in a variety of cell types. In resting cells, BimEL expression levels, the major and most abundant isoform, are controlled by Erk1/2-mediated phosphorylation, which targets BimEL for ubiquitination and degradation. We previously reported that TGFbeta induces the expression of the pro-apoptotic protein Bim through a Smad3-dependent mechanism to induce cell death in B-lymphocytes. A number of studies have shown TGFbeta to cause transcriptional induction of Bim in many cell types. Recently, we demonstrated that, in addition to its transcriptional effects on Bim, TGFbeta induces a MAPK phosphatase (MKP), MKP2/DUSP4, to rapidly increase BimEL levels by inactivation of Erk1/2, resulting in dephosphorylation and escape of BimEL from ubiquitin-mediated degradation. Our findings are of importance not only in the context that we implicate TGFbeta to increase BimEL levels through both an immediate post-translational regulatory mechanism and a long-term effect through transcriptional induction, but also in the context of implicating MKPs as regulatory players in apoptosis. Here we summarize these recent findings and their significance to our understanding of how TGFbeta mediates apoptosis, and we explore the possible regulatory mechanisms controlling Bim expression levels.