TGF beta-mediated BIM expression and apoptosis are regulated through SMAD3-dependent expression of the MAPK phosphatase MKP2.

ABSTRACT: Transforming growth factor-beta (TGFbeta) induces the expression of the pro-apoptotic protein BIM, and mediates apoptosis in hepatocytes and B lymphocytes. BIM is regulated through a post-translational mechanism involving ERK-dependent phosphorylation and ubiquitin-mediated proteasomal degradation. Here, we show that TGFbeta induces BIM through its rapid inhibition of ERK, thereby preventing the phosphorylation and degradation of BIM. TGFbeta, through a SMAD3-dependent mechanism, transcriptionally induces the mitogen-activated protein kinase (MAPK) phosphatase MKP2, encoded by an immediate early gene, to attenuate ERK and promote the accumulation of BIM protein. Overexpression of MKP2 in hepatocytes modulates ERK-mediated phosphorylation of BIM and apoptosis in the absence of TGFbeta, wher

SUBMITTER: Ramesh S 

PROVIDER: S-EPMC2572119 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature