Differential roles of JNK and Smad2 signaling pathways in the inhibition of c-Myc-induced cell death by TGF-beta

The transforming growth factor beta (TGF-beta) plays an important role in c onstraining cellular proliferation, but it is also a potent inducer of prog rammed cell death or apoptosis. Here, we demonstrate that TGF-beta can have an opposite effect, acting as a survival factor to prevent c-Myc-induced c ell death in Rat-1 fibroblasts, However, in marked contrast to TCF-beta, Sm ad2, which is a critical intracellular mediator of the TGF-beta signaling p athway, functions as an antagonist to induce increased cell death. The prot ective activity of TGF-beta was associated with the activation of c-Jun N-t erminal Kinase (JNK) and was not linked to the ability of TGF-beta to promo te cell cycle progression. Expression of dominant-interfering forms of vari ous components of the JNK signaling pathway, including Rac1, Cdc42, mitogen -activated protein kinase kinase 4 (MKK4), and c-Jun, abolished TGF-beta-me diated cell survival. Furthermore, overexpression of the constitutively act ivated mutant RacL61F37A, which selectively stimulates JNK cascade but not G1 cell cycle progression or actin polymerization, was sufficient to preven t apoptosis induced by c-Myc. These findings describe a differential effect of two separated signaling pathways of TGF-beta and indicate for the first time that Smad2 can act as antagonist to suppress TGF-beta-dependent cell survival.