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Nucleic Acids Research, 2000, Vol. 28, No. 21 4291-4298
© 2000 Oxford University Press

The transcriptional co-activator P/CAF potentiates TGF-ß/Smad signaling

Susumu Itoh*, Johan Ericsson1, Jun-ichi Nishikawa2, Carl-Henrik Heldin1 and Peter ten Dijke

The Netherlands Cancer Institute, Division of Cellular Biochemistry, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands, 1Ludwig Institute for Cancer Research, Biomedical Center, Box 595, S-751 24, Uppsala, Sweden and 2Laboratory of Environmental Biochemistry, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-Oka, Suita, Osaka 565-0871, Japan

Smads perform pivotal functions in the intracellular signaling of transforming growth factor-ß (TGF-ß). TGF-ß-mediated activation of TGF-ß type I receptor stimulates the phosphorylation of Smad2 and Smad3 and subsequent heteromeric complex formation with Smad4. The heteromeric Smad complexes translocate into the nucleus where they, in co-operation with co-activators and co-repressors, regulate transcriptional responses. Here we investigated the possible co-activator function of P/CAF in TGF-ß/Smad signaling. P/CAF was found to interact directly with Smad3 in vitro. Moreover, Smad2 and Smad3 interacted with P/CAF upon TGF-ß type I receptor activation in cultured mammalian cells. The interaction involves the MH2 domain of Smad3 and the N-terminal region of P/CAF. P/CAF potentiated the transcriptional activity of heterologous Gal4–Smad2 and Gal4–Smad3 fusion proteins. In addition, P/CAF potentiated the TGF-ß/Smad3-induced transcriptional responses, which could be further enhanced by co-activators p300 and Smad4. P/CAF may, therefore, activate Smad-mediated transcriptional responses independently or in co-operation with p300/CBP. Our results indicate a direct physical and functional interplay between two negative regulators of cell proliferation, Smad3 and P/CAF.

* To whom correspondence should be addressed. Tel: +31 20 512 1979; Fax: +31 20 512 1989; Email: sitoh@nki.nl


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