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Molecular and Cellular Biology, July 2003, p. 4494-4510, Vol. 23, No. 13
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.13.4494-4510.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Nuclear Factor YY1 Inhibits Transforming Growth Factor ß- and Bone Morphogenetic Protein-Induced Cell Differentiation

Keiko Kurisaki,^1, Akira Kurisaki,^1, Ulrich Valcourt,¹ Alexei A. Terentiev,^1, Katerina Pardali,¹ Peter ten Dijke,² Carl-Henrik Heldin,¹ Johan Ericsson,¹ and Aristidis Moustakas^1*

Ludwig Institute for Cancer Research, Biomedical Center, SE-751 24 Uppsala, Sweden,¹ Division of Cellular Biochemistry, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands²

Received 28 October 2002/ Returned for modification 19 December 2002/ Accepted 7 April 2003

Smad proteins transduce transforming growth factor ß (TGF-ß) and bone morphogenetic protein (BMP) signals that regulate cell growth and differentiation. We have identified YY1, a transcription factor that positively or negatively regulates transcription of many genes, as a novel Smad-interacting protein. YY1 represses the induction of immediate-early genes to TGF-ß and BMP, such as the plasminogen activator inhibitor 1 gene (PAI-1) and the inhibitor of differentiation/inhibitor of DNA binding 1 gene (Id-1). YY1 inhibits binding of Smads to their cognate DNA elements in vitro and blocks Smad recruitment to the Smad-binding element-rich region of the PAI-1 promoter in vivo. YY1 interacts with the conserved N-terminal Mad homology 1 domain of Smad4 and to a lesser extent with Smad1, Smad2, and Smad3. The YY1 zinc finger domain mediates the association with Smads and is necessary for the repressive effect of YY1 on Smad transcriptional activity. Moreover, downregulation of endogenous YY1 by antisense and small interfering RNA strategies results in enhanced transcriptional responses to TGF-ß or BMP. Ectopic expression of YY1 inhibits, while knockdown of endogenous YY1 enhances, TGF-ß- and BMP-induced cell differentiation. In contrast, overexpression or knockdown of YY1 does not affect growth inhibition induced by TGF-ß or BMP. Accordingly, YY1 does not interfere with the regulation of immediate-early genes involved in the TGF-ß growth-inhibitory response, the cell cycle inhibitors p15 and p21, and the proto-oncogene c-myc. In conclusion, YY1 represses Smad transcriptional activities in a gene-specific manner and thus regulates cell differentiation induced by TGF-ß superfamily pathways.

Present address: Department of Cytology, Institute for Enzyme Research, Tokushima University, Tokushima, Japan.

Present address: Institute of Problems of Chemical Physics RAS, Chernogolovka, Moscow Region 142432, Russia.

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