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Increased Susceptibility to Tumorigenesis of Ski-Deficient

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Increased Susceptibility to Tumorigenesis of Ski-Deficient Oncogene (2001) 20, 8100 ± 8108 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Increased susceptibility to tumorigenesis of ski-de®cient heterozygous mice Toshie Shinagawa1, Teruaki Nomura1, Clemencia Colmenares2, Miki Ohira3, Akira Nakagawara3 and Shunsuke Ishii*,1 1Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, and CREST (Core Research for Evolutionary Science and Technology) Research Project of JST (Japan Science & Technology Corporation), 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan; 2Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio, OH 44195, USA; 3Division of Biochemistry, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba City, Chiba 260-8717, Japan The c-ski proto-oncogene product (c-Ski) acts as a co- Introduction repressor and binds to other co-repressors N-CoR/ SMRT and mSin3A which form a complex with histone The v-ski gene was originally identi®ed as the deacetylase (HDAC). c-Ski mediates the transcriptional transforming gene of the avian Sloan-Kettering retro- repression by a number of repressors, including nuclear viruses, which transform chicken embryonic ®broblasts hormone receptors and Mad. c-Ski also directly binds to, (Li et al., 1986). The cellular homologue c-ski has been and recruits the HDAC complex to Smads, leading to identi®ed from several species, including human, inhibition of tumor growth factor-b (TGF-b) signaling. chicken, and Xenopus (Nomura et al., 1989; Stavnezer This is consistent with the function of ski as an et al., 1989; Sutrave and Hughes, 1989; Sleeman and oncogene. Here we show that loss of one copy of c-ski Laskey, 1993). The chicken c-ski proto-oncogene increases susceptibility to tumorigenesis in mice. When products (c-Ski) are nuclear proteins of 750 amino challenged with a chemical carcinogen, c-ski hetero- acids (Stavnezer et al., 1989; Sutrave and Hughes, zygous mice showed an increased level of tumor 1989; Sutrave et al., 1990a). The ski gene family formation relative to wild-type mice. In addition, c-ski- contains another member, sno (ski-related novel) gene de®cient mouse embryonic ®broblasts (MEFs) had (Nomura et al., 1989). The sno gene also has increased proliferative capacity, whereas overexpression transforming capacity, and overexpression of sno leads of c-Ski suppressed the proliferation. Furthermore, the to transformation of chicken embryo ®broblasts (Boyer introduction of activated Ki-ras into c-ski-de®cient et al., 1993). Ski is a unique oncogene in that, in MEFs resulted in neoplastic transformation. These addition to aecting cell growth, it is also involved in ®ndings demonstrate that c-ski acts as a tumor regulation of muscle dierentiation. Overexpression of suppressor in some types of cells. The level of cdc25A Ski induces muscle dierentiation in embryo ®broblasts mRNA, which is down regulated by two tumor (Colmenares and Stavnezer, 1989; Colmenares et al., suppressor gene products, Rb and Mad, was upregulated 1991) and causes postnatal hypertrophy of type II fast in c-ski-de®cient MEFs, whereas it decreased by over- muscle ®bers in transgenic mice (Sutrave et al., 1990b). expressing c-Ski in MEFs. This is consistent with the Furthermore, mice lacking c-ski display decreased fact that c-Ski acts as a co-repressor of Mad and Rb. myo®ber development in addition to abnormalities in These results support the view that the decreased pattern formation such as defects in neuronal and activities of Mad and Rb in ski-de®cient cells at least craniofacial patterning (Berk et al., 1997). Thus, c-Ski partly contribute to enhanced proliferation and suscept- has the multiple roles in the regulation of cellular ibility to tumorigenesis. Human c-ski gene was mapped proliferation and development. to a region close to the p73 tumor suppressor gene at the c-Ski is localized to the nucleus (Sutrave et al., 1990a) 1p36.3 locus, which is already known to contain multiple and binds to DNA in association with other cellular uncharacterized tumor suppressor genes. Oncogene factors (Nagase et al., 1990). Ski can function as a (2001) 20, 8100 ± 8108. transcriptional repressor via the speci®c DNA sequence (Nicol and Stavnezer, 1998). Recently we demonstrated Keywords: co-repressor; Ski/Sno; tumor suppressor; that c-Ski and Sno act as co-repressors (Nomura et al., Mad; Rb 1999). c-Ski directly binds to the two co-repressors N- CoR/SMRT (HoÈ rlein et al., 1995; Chen and Evans, 1995) and mSin3A (Ayer et al., 1995). mSin3A and N- CoR/SMRT also interact each other, and form a macromolecular complexes with histone deacetylase (HDAC), respectively (Heinzel et al., 1997; Alland et al., 1997; Hassing et al., 1997; Laherty et al., 1997; *Correspondence: S Ishii; E-mail: [email protected] Received 9 April 2001; revised 12 September 2001; accepted 18 Nagy et al., 1997). Ski and Sno are required for September 2001 transcriptional repression by multiple repressors in- ski acts as a tumor suppressor in mice T Shinagawa et al 8101 cluding Mad and thyroid hormone receptor b (Nomura repression by Mad and Rb (Nomura et al., 1999; et al., 1999), and modulate the transcriptional regula- Tokitou et al., 1999) suggest that ski may function as tion mediated by retinoid receptor a (Dahl et al., 1998). a tumor suppressor at least in some types of cells. The multiple roles of c-Ski described above in the To investigate the possibility that ski acts as a regulation of cellular proliferation and development tumor suppressor, we analysed the ski heterozygous may re¯ect the capacity of Ski to associate with a wide mutant mice. Here we demonstrate that loss of one range of dierent transcriptional regulators. In contrast copy of ski increases susceptibility to tumorigenesis to the role of c-Ski in the transcriptional repression in mice. elicited by multiple repressors, c-Ski also binds to transcriptional activator and inhibits its activity. c-Ski was recently demonstrated to directly bind to Smad Results proteins and recruits the HDAC complex to Smad proteins, leading to the inhibition of Smad proteins- Tumor susceptibility of ski+/7 mice dependent transcriptional activation (Sun et al., 1999; Luo et al., 1999; Akiyoshi et al., 1999; Xu et al., 2000). To examine the possibility that ski might act as a Smad proteins induce the transcription of a group of tumor suppressor, we compared the tumor suscept- target genes upon TGF-b stimulation (for a review, see ibility of ski+/7 mice and wild-type littermates during Massague and Wotton, 2000), indicating that c-Ski a course of intraperitoneal injections of the carcino- negatively regulates TGF-b signaling. Since TGF-b gen 9,10-dimethyl-1,2-benzanthracene (DMBA). Over inhibits cellular proliferation at least partly by inducing an observation period of 90 days, 96% of the wild- the expression of the Cdk4/6 inhibitor p15INK4B type male mice (n=23), 91% of the wild-type female (Hannon and Beach, 1994), this ®nding is consistent mice (n=22), 52% of the ski+/7 male mice (n=21), with the view that ski possesses the transforming and 30% of the ski+/7 female mice (n=20) survived capacity of an oncogene. this treatment and remained free of clinically- In contrast to its function as an oncogene, c-Ski is apparent tumors (P50.001) (Figure 1a). In total, 23 required to mediate transcriptional repression by two ski+/7 mice died with grossly-visible tumors, most of tumor suppressors, Mad and Rb (Nomura et al., which were malignant lymphomas as judged by 1999; Tokitou et al., 1999). Mad proteins, containing Giemsa staining and immunostaining. Twenty mice the bHLH domain, acts as transcriptional repressors developed lymphomas. Of these, ®fteen were T-cell, after heterodimerization with Max (Ayer et al., 1993). one was B cell, and four were of indeterminate origin The same target sequence of Mad/Max is also (negative for the T-cell and B-cell markers of CD3, recognized by a heterodimer of Myc/Max, which Thy 1.2, B220, and IgM). Two mice developed activates transcription. Myc/Max enhances cellular myelocytic leukemia and one mouse developed proliferation or transformation, whereas Mad/Max megakaryocytic leukemia. Histological analysis of leads to suppression of proliferation or induction of lymphomas in ski+/7 mice homogeneously expressing terminal dierentiation (Ayer and Eisenman, 1993; the T-cell marker Thy-1.2 (T lymphomas) is shown in Roussel et al., 1996; Chin et al., 1995). The role of Figure 1b. Mad as a tumor suppressor was demonstrated by the Most of the tumor suppressors examined to date observation that mutant mice lacking mxi1, a member ful®l Knudson's `two-mutation' criterion (Knudson, of the mad gene family, showed increased suscept- 1971, 1997), which dictates that loss of the wild-type ibility to tumorigenesis (Schreiber-Agus et al., 1998). allele or impaired expression of the tumor suppressor The product of the Rb tumor suppressor gene protein causes tumorigenesis in cells that normally negatively regulates the G1/S transition in the cell express the tumor suppressor gene. Studies of various cycle by silencing a group of target genes regulated by tumor suppressor genes have indicated that loss of E2F transcription factors (for a review, see Weinberg, expression from the wild-type allele is caused by 1995; Nevins, 1992). Rb recruits the HDAC complex multiple mechanisms including rearrangement or to E2F, and actively represses the transcription of deletion of the gene, point mutation, and methylation. S phase-speci®c genes (Brehm et al., 1998; Magnaghi- To determine whether expression of Ski protein from Jaulin et al., 1998; Luo et al., 1998). Thus, Mad and the wild-type allele in ski+/7 mice was lost in tumors, Rb play an important role in the negative regulation we carried out immunostaining of Ski protein in of the G1/S transition.
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