期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：17
页码：9791-9796
DOI：10.1073/pnas.1733973100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Smad proteins mediate transforming growth factor {beta} (TGF-{beta})-inducible transcriptional responses. Protein inhibitor of activated signal transducer and activator of transcription (PIAS) represents a family of proteins that inhibits signal transducer and activator of transcription and also regulates other transcriptional responses. In an effort to identify Smad-interacting proteins by a yeast three-hybrid screen with Smad3 and Smad4 as baits, we identified PIASy, a member of the PIAS family. In yeast, PIASy interacts strongly with Smad4 and also with receptor-regulated Smads. In mammalian cells, PIASy binds most strongly with Smad3 and also associates with other receptor-regulated Smads and Smad4. The interaction between Smad3 and PIASy is increased in the presence of TGF-{beta} and occurs through the C-terminal domain of Smad3. Moreover, Smad3, Smad4, and PIASy can form a ternary complex. PIASy does not inhibit Smad complex binding to DNA, but it represses Smad transcriptional activity. Interestingly, conditional overexpression of PIASy selectively inhibits a subset of endogenous TGF-{beta}-responsive genes, which includes the cyclin-dependent kinase inhibitor p15, and the plasminogen activator inhibitor 1. We further show that PIASy can interact constitutively with histone deacetylase 1 (HDAC1) and that addition of HDAC inhibitor trichostatin A (TSA) can prevent the inhibitory function of PIASy. Taken together, our studies indicate that PIASy can inhibit TGF-{beta}/Smad transcriptional responses through interactions with Smad proteins and HDAC.
