Induction of apoptosis by DPC4, a transcriptional factor regulated by transforming growth factor-beta through stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) signaling pathway

Abstract

Many of the actions of serine/threonine kinase receptors for the transforming growth factor-beta (TGFbeta) are mediated by DPC4, a human MAD-related protein identified as a tumor suppressor gene in pancreatic carcinoma. Overexpression of DPC4 is sufficient to induce the activation of gene expression and cell cycle arrest, characteristic of the TGFbeta response. The stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) is also one of the downstream targets required for TGFbeta-mediated signaling. Here we report that expression of the dominant-interfering mutant of various components of the SAPK/JNK cascade specifically blocked both TGFbeta and DPC4-induced gene expression. These dominant-interfering mutants also inhibited TGFbeta-stimulated DPC4 transcriptional activity. Moreover, we find that overexpression of DPC4 causes transfected cells to undergo the morphological changes typical of apoptosis. These findings define a mechanism whereby TGFbeta signals mediated by DPC4 and SAPK/JNK cascade are integrated in the nucleus to activate gene expression and identify a new cellular function for DPC4.