TGFbeta activates mitogen- and stress-activated protein kinase-1 (MSK1) to attenuate cell death.

ABSTRACT: Transforming growth factor-β (TGFβ) binding to its receptor leads to intracellular phosphorylation of Smad2 and Smad3, which oligomerize with Smad4. These complexes accumulate in the nucleus and induce gene transcription. Here we describe mitogen- and stress-activated kinase 1 (MSK1) as an antagonist of TGFβ-induced cell death. Induction of MSK1 activity by TGFβ depends on Smad4 and p38 MAPK activation. Knockdown of GADD45, a Smad4-induced upstream regulator of p38 MAPK prevents TGFβ-induced p38 and MSK1 activity. MSK1 functionally regulates pro-apoptotic BH3-only BCL2 proteins, as MSK1 knockdown reduces Bad phosphorylation and enhances Noxa and Bim expression, leading to enhanced TGFβ-induced caspase-3 activity and cell death. This finding suggests that MSK1 represents a pro-survival path

SUBMITTER: van der Heide LP 

PROVIDER: S-EPMC3037612 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature