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The C Terminus of the Synovial Sarcoma-Associated SSX Proteins Interacts with the LIM Homeobox Protein LHX4

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The C Terminus of the Synovial Sarcoma-Associated SSX Proteins Interacts with the LIM Homeobox Protein LHX4 Oncogene (2008) 27, 653–662 & 2008 Nature Publishing Group All rights reserved 0950-9232/08 $30.00 www.nature.com/onc ORIGINAL ARTICLE The C terminus of the synovial sarcoma-associated SSX proteins interacts with the LIM homeobox protein LHX4 DRH de Bruijn, AHA van Dijk, MP Willemse and A Geurts van Kessel Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands As a result of the synovial sarcoma-associated t(X;18) Introduction translocation, the SS18 gene on chromosome 18 is fused to either one of the three closely related SSX genes on the Synovial sarcoma is an aggressive soft tissue tumor X chromosome. The SS18 protein is thought to act as a predominantly affecting children and young adults. transcriptional co-activator, whereas the SSX proteins are Cytogenetically, it is characterized by a recurring thought to act as transcriptional corepressors. The main chromosomal translocation, t(X;18)(p11;q11), which is SSX-repression domain is located in its C terminus, a found in more than 95% of all cases (dos Santos et al., domain that is retained in the respective SS18–SSX fusion 2001; Ladanyi et al., 2002). As a result of this proteins. Both the SS18 and SSX proteins lack DNA- translocation, the SS18 gene (previously called SYT) binding domains. Previously, we found that the SS18 and on chromosome 18 is fused to either one of the three SS18–SSX fusion proteins may be tethered to DNA closely related SSX genes on the X chromosome, SSX1, targets via the SS18-interacting protein AF10. Here, we SSX2 or SSX4 (Clark et al., 1994; Crew et al., 1995; de set out to isolate proteins that interact with the SSX Leeuw et al., 1995; Skytting et al, 1999). The occurrence C-terminal repression domain using a yeast two-hybrid of either SS18–SSX1 or SS18–SSX2 fusions was found interaction trap. Of the positive clones isolated, two to correlate to histologic (de Leeuw et al., 1994) and/or corresponded to the LIM homeobox protein LHX4, a prognostic (Kawai et al., 1998; Ladanyi et al., 2002) DNA-binding protein that is involved in transcription parameters, although the latter observation could not be regulation. An endogenous interaction was subsequently confirmed (Guillou et al., 2004). established in mammalian cells via colocalization and The SS18 gene is well conserved over evolution and is coimmunoprecipitation of the respective proteins. Inter- expressed widely in embryonic and adult tissues (de estingly, the LHX4 gene was previously found to be Bruijn et al., 1996; 2001b). The human SS18 protein deregulated in various human leukemias. In addition, it resides in the nucleus where it displays a distinct was previously found that LIM homeobox proteins may punctate pattern (Brett et al., 1997; dos Santos et al., bind to and activate the glycoprotein-a (CGA) promoter. 1997). The SS18 protein is a modular protein, consisting Using LHX4 chromatin immunoprecipitation and CGA- of two functional domains, the SS18 N-terminal promoter assays, we found that endogenous LHX4 binds homology (SNH) domain and the glutamine, proline, to the CGA promoter and that LHX4-mediated CGA glycine and tyrosine-rich QPGY domain (Thaete et al., activation is enhanced by the SS18–SSX protein, but not 1999; de Bruijn et al., 2001a). Of these, the SNH domain by the SSX protein. Taken together, we conclude that this directly interacts with the acute leukemia-associated novel protein – protein interaction may have direct transcription factor AF10 (de Bruijn et al., 2001a), the consequences for the (de)regulation of SSX and/or SWI/SNF ATPases BRM and BRG1 (Thaete et al., SS18–SSX target genes and, thus, for the development 1999; Perani et al., 2003; de Bruijn et al., 2006), the of human synovial sarcomas. histone acetyltransferase p300 (Eid et al., 2000) and the Oncogene (2008) 27, 653–662; doi:10.1038/sj.onc.1210688; corepressor mSin3A (Ito et al., 2004). Indirectly, the published online 30 July 2007 SS18 protein associates with yet another SWI/SNF protein, INI1 (Debernardi et al., 2002; Kato et al., Keywords: synovial sarcoma; SSX; LHX4; SS18–SSX; 2002). The QPGY domain is a transcriptional co- transcription regulation activation domain and mediates multimerization of the SS18 protein (Brett et al., 1997; Thaete et al., 1999; Perani et al., 2003). Together, these findings indicate that the SS18 protein acts as transcriptional co-activator through chromatin modification mechanisms (de Bruijn et al., 2006). Correspondence: Dr A Geurts van Kessel, Department of Human The SSX genes constitute a family of at least nine Genetics 855, Radboud University Nijmegen Medical Centre, PO Box members which are located in two clusters on the X 9101, 6500 HB Nijmegen, The Netherlands. E-mail: [email protected] chromosome (de Leeuw et al., 1996; Gure et al., 1997; Received 3 January 2007; revised 13 June 2007; accepted 15June 2007; dos Santos et al., 2000b). All SSX genes encode proteins published online 30 July 2007 of 188 amino acids, which are rich in charged amino The SSX C terminus interacts with LHX4 DRH de Bruijn et al 654 acids and contain an acidic C-terminal tail. Normal SSX colocalization studies, we and others have found that expression has been found in testis and, at a low level, in the SSXRD is responsible for (i) SSX nuclear localiza- thyroid (Crew et al., 1995; de Leeuw et al., 1996; Gure tion, (ii) colocalization with PcG proteins, (iii) associa- et al., 1997, 2002). Ectopic SSX expression has been tion with mitotic chromosomes, and (iv) association observed in various tumor types, in particular in human with core histones (dos Santos et al., 2000a; Kato et al., melanomas (Tureci et al., 1998, 1996; dos Santos et al., 2002). Through yeast two-hybrid screening, we have 2000b). Homology between the SSX family members is previously identified the SSX2IP (also known as ADIP) high, ranging from 88 to 95% at the protein level. The and RAB3IP proteins as in vivo interactors of the SSX SSX proteins were found to repress transcription in KRAB-like domain (de Bruijn et al., 2002). Since no reporter assays (Brett et al., 1997; Thaete et al., 1999). direct interactions between SSX and any of the PcG Part of this activity was mediated by the N-terminal proteins have been demonstrated, we assume that other SSX moiety that exhibits homology to the family of proteins mediate the observed associations between SSX Kru¨ ppel-associated box (KRAB) repression domains, and PcG proteins. Taken together, these data suggest which were recently associated with heterochromatin that the SSX proteins function as transcriptional (Huntley et al., 2006; Vogel et al., 2006). However, corepressors, and exert these functions through interac- considerably stronger repression was achieved by the tions with, as yet, unknown DNA-binding proteins. SSX C-terminal 34 amino acids, which was therefore In the majority of SS18–SSX fusion proteins char- designated SSX-repression domain (SSXRD; Figure 1). acterized to date, the C-terminal eight amino acids of This acidic domain (pI 4.8) does not display obvious the SS18 protein are replaced by the C-terminal 78 homologies to known protein domains, but exhibits a amino acids of one of the SSX proteins (Clark et al., high degree of similarity between the various SSX family 1994; Crew et al., 1995; de Leeuw et al., 1995). As a members (Lim et al., 1998; dos Santos et al., 2000a). consequence, the SS18 QPGY domain is interrupted and Immediately upstream of the SSXRD, a divergent the complete KRAB domain of SSX is lost. The main domain (DD) has been defined that exhibits the highest body of the SS18 protein, including the SNH domain, is degree of divergence between the various SSX family fused to the highly polar C-terminal SSX tail, including members (dos Santos et al., 2000a). Although there is no the SSX-divergent (SXXDDs) and SSXRDs. This fusion evidence to suggest that the SSX proteins can bind DNA has been associated with neoplastic transformation directly, all SSX proteins are localized in the nucleus, (Nagai et al., 2001) and changes in the epigenetic being both diffusely distributed and concentrated in makeup of target genes (de Bruijn et al., 2006). Another nuclear dots (Brett et al., 1997; dos Santos et al., 1997, recent study indicated that the SS18–SSX1 and SS18– 2000a; Soulez et al., 1999). These dots have been found SSX2 fusion proteins interact preferentially with the to also harbor several members of the polycomb group transcription factors Snail and Slug, respectively (Saito (PcG) proteins, that is, HPC2, BMI1 and RING1 (Lim et al., 2006). These interactions were shown to be et al., 1998; dos Santos et al., 2000a). In line with the specific for the fusion proteins and might provide an transcriptional repressor function(s) of the SSX pro- explanation for the (disputed) correlation between teins, PcG proteins form multi-protein complexes that fusion type and histologic appearance (Guillou et al., maintain the repressed state of target genes by inducing 2004). Here, we have searched for interacting proteins changes in chromatin structure (Schuettengruber et al., through yeast two-hybrid screening using the SSX1 2007; Schwartz and Pirrotta, 2007). Through cellular C-terminal domains DD and SSXRD as a bait. Our Figure 1 (a) Diagram depicting the SS18, SSX1 and LHX4 proteins with their annotated functional domains (see text). The arrowheads above the SS18 and SSX1 proteins mark the locations of the respective synovial sarcoma-associated break points. The solid lines below the SSX1 and LHX4 proteins represent the SSX1 bait fragment and the two independent LHX4 prey fragments that were isolated in the yeast two-hybrid screen. (b) Diagram depicting the LHX4 fragments which were used as baits in the yeast two- hybrid screen.
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