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.
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.
Perani
Michela
M
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. michela.perani@icr.ac.uk
Antonson
Per
P
Hamoudi
Rifat
R
Ingram
Catherine J E
CJ
Cooper
Colin S
CS
Garrett
Michelle D
MD
Goodwin
Graham H
GH
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000737:chemistry*; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002522:Chlorocebus aethiops; D002843:Chromatin / Q000737:chemistry; D003001:Cloning, Molecular; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D004330:Drosophila; D015723:Gene Library; D005973:Glutamine / Q000737:chemistry; D005982:Glutathione Transferase / Q000378:metabolism; D005998:Glycine / Q000737:chemistry; D006728:Hormones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008954:Models, Biological; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry*; D010957:Plasmids / Q000378:metabolism; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D012326:RNA Splicing; D034802:RNA-Binding Protein EWS / Q000737:chemistry*; D034702:RNA-Binding Protein FUS / Q000737:chemistry*; D016601:RNA-Binding Proteins / Q000737:chemistry*; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism*; D013584:Sarcoma, Synovial / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D000068103:Serine-Arginine Splicing Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014178:Translocation, Genetic; D020798:Two-Hybrid System Techniques; D014443:Tyrosine / Q000737:chemistry
D018797:Cell Cycle Proteins; D002843:Chromatin; D018076:DNA, Complementary; D006728:Hormones; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; C436317:RBM14 protein, human; D034802:RNA-Binding Protein EWS; D034702:RNA-Binding Protein FUS; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C115188:SRSF10 protein, human; C093961:SS18 protein, human; D005973:Glutamine; D000068103:Serine-Arginine Splicing Factors; D014443:Tyrosine; D011392:Proline; D005982:Glutathione Transferase; D005998:Glycine