title: TGF-β induces p53/Smads complex formation in the PAI-1 promoter to activate transcription.
abstract: 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.
authors.affiliation: Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, 467-8603 Nagoya, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kawarada
authors.affiliation: Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, 467-8603 Nagoya, Japan.|Department of Innovative Therapeutics Sciences, Cooperative major in Nanopharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, 467-8603 Nagoya, Japan.
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, 467-8603 Nagoya, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Kawasaki
authors.affiliation: Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, 467-8603 Nagoya, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Fukuura
authors.affiliation: Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, 467-8603 Nagoya, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, 467-8603 Nagoya, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, 467-8603 Nagoya, Japan.|Department of Innovative Therapeutics Sciences, Cooperative major in Nanopharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, 467-8603 Nagoya, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, 467-8603 Nagoya, Japan.|Department of Innovative Therapeutics Sciences, Cooperative major in Nanopharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, 467-8603 Nagoya, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Hayashi
mesh_terms: D002460:Cell Line; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020218:Response Elements; D012795:Sialoglycoproteins / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; D012795:Sialoglycoproteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; C571744:bone sialoprotein (35-62), human