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J. Biol. Chem., Vol. 280, Issue 52, 42863-42876, December 30, 2005

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The Proto-oncoprotein SYT Interacts with SYT-interacting Protein/Co-activator Activator (SIP/CoAA), a Human Nuclear Receptor Co-activator with Similarity to EWS and TLS/FUS Family of Proteins^*

Michela Perani1, Per Antonson2, Rifat Hamoudi3, Catherine J. E. Ingram4, Colin S. Cooper, Michelle D. Garrett, and Graham H. Goodwin

From the Section of Molecular Carcinogenesis, Institute of Cancer Research and Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, United Kingdom

The proto-oncoprotein SYT is involved in the unique translocation t(X;18) found in synovial sarcoma SYT-SSX fusions. SYT has a conserved N-terminal domain (SNH domain) that interacts with the human paralog of Drosophila Brahma (hBRM) and Brahma-related gene 1 (BRG1) chromatin remodeling proteins and a C-terminal transactivating sequence rich in glutamine, proline, glycine, and tyrosine (QPGY domain). Here we reported the isolation of the ribonucleoprotein SYT-interacting protein/co-activator activator (SIP/CoAA), which specifically binds the QPGY domain of SYT and also the SYT-SSX2 translocation fusion. SIP/CoAA is a general nuclear co-activator and an RNA splicing modulator that contains two RNA recognition motifs and multiple hexapeptide repeats. We showed that the region consisting of the hexapeptide motif (YQ domain) is similar to the hexapeptide repeat domain found in EWS and in TLS/FUS family proteins. The YQ domain also resembles the QPGY region of SYT itself and like all these other domains acts as a transcriptional activator in reporter assays. Most interestingly, the last 84 amino acids adjacent to YQ down-modulate by 25-fold the YQ transactivation of the reporter gene, and both domains are important for SIP/CoAA binding to SYT. In addition, SYT acts together with SIP/CoAA in stimulating estrogen and glucocorticoid receptor-dependent transcriptional activation. Activation is hormone-dependent and requires functional hBRM and/or BRG1. The stimulation is strongly reduced if the N-terminal region of hBRM/BRG1 (amino acids 1–211) is deleted. This region encompasses the SNF11 binding domain (amino acids 156–211), which interacts specifically with SYT in vivo and in vitro.

Received for publication, March 17, 2005 , and in revised form, October 7, 2005.

^* This work was supported by the Cancer Research UK and the Association of International Cancer Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF080561 [GenBank] .

² Present address: Dept. of Biosciences Karolinska Institutet, Novum, S-14157 Huddinge, Sweden.

³ Present address: Division of Molecular Histopathology, Dept. of Pathology, Addenbrooke's Hospital, University of Cambridge, Hills Rd., Cambridge CB2 2QQ, UK.

⁴ Present address: Galton Laboratory, Dept. of Biology, University College London, Wolfson House, 4 Stephenson Way, London NW1 2HE, UK.

¹ To whom correspondence should be addressed: Section of Molecular Carcinogenesis, Brookes Lawley Bldg., Institute of Cancer Research, 15 Cotswold Rd., Sutton, Surrey SM2 5NG, UK. Tel.: 44-20-8722-4198; Fax: 44-20-8722-4052; E-mail: michela.perani{at}icr.ac.uk.

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