TGF-β induces p53/Smads complex formation in the PAI-1 promoter to activate transcription

• Published in: Scientific reports 2016-10, Vol.6 (1), p.35483-35483, Article 35483
• Main Authors: Kawarada, Yuki, Inoue, Yasumichi, Kawasaki, Fumihiro, Fukuura, Keishi, Sato, Koichi, Tanaka, Takahito, Itoh, Yuka, Hayashi, Hidetoshi
• Format: Article
• Language: English
• Subjects: 38/89; 38/90; 631/337/572; 631/45/127/1219; 82/29; 96/21; Cell Line; Humanities and Social Sciences; Humans; multidisciplinary; Multiprotein Complexes - metabolism; Peptide Fragments - metabolism; Plasminogen Activator Inhibitor 1 - genetics; Promoter Regions, Genetic; Protein Binding; Protein Interaction Domains and Motifs; Response Elements; Science; Sialoglycoproteins - metabolism; Signal Transduction; Smad Proteins - chemistry; Smad Proteins - metabolism; Transcriptional Activation; Transforming Growth Factor beta - metabolism; Tumor Suppressor Protein p53 - chemistry; Tumor Suppressor Protein p53 - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep35483

Transforming growth factor β (TGF-β) signaling facilitates tumor development during the advanced stages of tumorigenesis, but induces cell-cycle arrest for tumor suppression during the early stages. However, the mechanism of functional switching of TGF-β is still unknown, and it is unclear whether inhibition of TGF-β signaling results amelioration or exacerbation of cancers. Here we show that the tumor suppressor p53 cooperates with Smad proteins, which are TGF-β signal transducers, to selectively activate plasminogen activator inhibitor type-1 (PAI-1 ) transcription. p53 forms a complex with Smad2/3 in the PAI-1 promoter to recruit histone acetyltransferase CREB-binding protein (CBP) and enhance histone H3 acetylation, resulting in transcriptional activation of the PAI-1 gene. Importantly, p53 is required for TGF-β-induced cytostasis and PAI-1 is involved in the cytostatic activity of TGF-β in several cell lines. Our results suggest that p53 enhances TGF-β-induced cytostatic effects by activating PAI-1 transcription, and the functional switching of TGF-β is partially caused by p53 mutation or p53 inactivation during cancer progression. It is expected that these findings will contribute to optimization of TGF-β-targeting therapies for cancer.