Oncogenic protein provokes cell cycle arrest termed premature senescence. In this process Ras has been known to induce cyclin-dependent kinase inhibitor (CKI) p16INK4A in primary fibroblasts. Here, we present a novel finding that human chimeric oncoprotein SYT-SSX1 induces CKI p21WAF1/CIP1 (p21) for suppression of cell growth. In human synovial sarcoma cell lines, the expression levels of p21 were high and the transcriptional activity of the p21 gene promoter was significantly elevated. The transient expression of SYT-SSX1-induced activation of the p21 gene promoter in human diploid fibroblasts. The N-terminus deletion form of SYT-SSX1, which failed to bind to hBRM one of the chromatin remodeling factors, preserved the p21 induction ability. This effect of SYT-SSX1 was similar in extent in both wild-type and p53-deficient HCT116 cell lines. Furthermore, the introduction of mutation in Sp1/Sp3 binding sites of the p21 gene promoter abolished the SYT-SSX1-induced transcriptional activity of its promoter. In SW13 cells, the stable expression of SYT-SSX1 suppressed cell growth in culture. These results suggest that SYT-SSX1 is able to induce p21 in a manner independent on hBRM and p53 but dependent on Sp1/Sp3.
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We thank Michiyuki Matsuda (Osaka University) for useful discussion, M Tada (Hokkaido University) for the p53 expression plasmid; B Vogelstein (Johns Hopkins University, Baltimore, MD, USA) for the HCT116 cell line and its p53−/− derivative; K I Nakayama (Kyushu University, Fukuoka, Japan) for advice on the isolation of MEFs; H Hiraga (Sapporo National Hospital, Sapporo, Japan) for antibodies to SSX1; W W Hall (University College Dublin, Ireland) for critical reading of the manuscript; and M Higuchi for technical assistance. This work was supported in part by a grant from the Ministry of Education, Science, Sports Culture and Technology of Japan, by Comprehensive Research on Aging and Health from the Ministry of Health, Labour and Welfare of Japan and by Yasuda Medical Research Foundation.
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Tsuda, M., Watanabe, T., Seki, T. et al. Induction of p21WAF1/CIP1 by human synovial sarcoma-associated chimeric oncoprotein SYT-SSX1. Oncogene 24, 7984–7990 (2005). https://doi.org/10.1038/sj.onc.1208942