Transcriptional repression of the transforming growth factor-␤ (TGF-␤) type II receptor (T␤RII) gene is one of several mechanisms leading to TGF-␤ resistance.Previously, we have shown that MS-275, a synthetic inhibitor of histone deacetylase (HDAC), specifically induces the expression of the T␤RII gene and restores the TGF-␤ signaling in human breast cancer cell lines. However, little is known about the mechanism by which inhibition of HDAC activates T␤RII expression. MS-275 treatment of cells expressing a wild-type T␤RII promoter/luciferase construct resulted in a 10-fold induction of the promoter activity. DNA transfection and an electrophoretic mobility shift assay showed that the induction of the T␤RII promoter by MS-275 requires the inverted CCAAT box and its cognate binding protein, NF-Y. In addition, a DNA affinity pull-down assay indicated that the PCAF protein, a transcriptional coactivator with intrinsic histone acetyltransferase (HAT) activity, is specifically recruited to the NF-Y complex in the presence of either MS-275 or trichostatin A. Based on these results, we suggest that treatment with the HDAC inhibitor induces T␤RII promoter activity by the recruitment of the PCAF protein to the NF-Y complex, interacting with the inverted CCAAT box in the T␤RII promoter.The histone-modifying enzymes histone acetyltransferase (HAT) 1 and histone deacetylase (HDAC) have been proposed to play an important role in transcriptional regulation by altering chromatin structure (1, 2). HATs specifically catalyze the acetylation of the ⑀-amino group of lysine residues at the Nterminal domain of histone H2A, H2B, H3, and H4, leading to a destabilization of the nucleosome structure whereas HDACs remove the acetyl group, resulting in a compact chromatin configuration. Hyperacetylation of chromatin is generally associated with transcriptional activation, whereas hypoacetylation of chromatin is associated with transcriptional repression (3, 4). HATs and HDACs thus constitute important links between chromatin structure and transcriptional output.Transforming growth factor ␤ (TGF-␤) has been implicated in a wide variety of cellular processes, including regulation of the cell cycle, cell differentiation, and extracellular matrix synthesis (5, 6). TGF-␤ primarily exerts its biological effects through interactions with the TGF-␤ type II receptor (T␤RII) (7,8). Much work (9 -12) has shown that inactivation of T␤RII contributes to malignant transformation at an early step of tumorigenesis and that it can occur through mutation or transcriptional repression of the T␤RII gene. Interestingly, many human cancer cell lines express normal T␤RII and downstream signaling intermediates, but express significantly low or undetectable levels of T␤RII mRNA, suggesting that transcriptional repression of the T␤RII gene might be a more common mechanism leading to TGF-␤ resistance (9,13,14).We have previously demonstrated (15) that MS-275, a histone deacetylase inhibitor, induces the accumulation of acetylated histones in the chromatin of the T␤R...

Smad7 inhibits responses mediated by transforming growth factor ␤ (TGF-␤) and acts in a negativefeedback loop to regulate the intensity or duration of the TGF-␤ signal. However, the aberrant expression and continued presence of Smad7 may cause TGF-␤ resistance. Here we report that Jab1/CSN5, which is a component of the COP9 signalosome complex, associates constitutively with Smad7 and that overexpression of Jab1/CSN5 causes the translocation of Smad7 from the nucleus to the cytoplasm, promoting its degradation. Overexpression of Jab1/CSN5 increases Smad2 phosphorylation and enhances TGF-␤-induced transcriptional activity. The inhibition of endogenous Jab1/CSN5 expression by small interfering RNA (siRNA) induces Smad7 expression. This study thus defines Jab1/CSN5 as an adapter that targets Smad7 for degradation, thus releasing Smad7-mediated suppression of TGF-␤ signaling.