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The transforming growth factor (TGF) signaling pathway is an essential pathway whose initiation results in cell growth arrest in most epithelial cells. Activation of TGF receptors leads to the phosphorylation and translocation of the Smad proteins, the major TGF intracellular signaling molecule, to the nucleus where transcription of TGF target genes occur. Many breast cancers contain aberrations in the regulation of Smad proteins demonstrating the importance of TGF signaling. Therefore, understanding how posttranslational modifications may regulate this pathway will increase our knowledge of how a normal cell becomes cancerous and may provide insight into novel therapeutics. This proposal suggests a series of experiments designed to study the acetylation of Smad proteins. We have determined that Smad2 can be efficiently acetylated by the acetyltransferase protein p300 in vivo and in vitro and that this acetylation is necessary for the transcriptional activity of the protein in Smad2-deficient mouse embryonic fibroblasts. This decrease in transcriptional activity is due to the inability of non-acetylated Smad2 to accumulate in the nucleus upon TGF treatment and translates into marked decrease in the TGF induced cell cycle arrest that is essential for the tumor suppressing ability of the TGF signaling pathway.