Analysis of transforming activity of human synovial sarcoma-associated chimeric protein SYT-SSX1 bound to chromatin remodeling factor hBRM/hSNF2 alpha.
Human synovial sarcoma has been shown to exclusively harbor the chromosomal translocation t(X;18) that produces the chimeric gene SYT-SSX. However, the role of SYT-SSX in cellular transformation remains unclear. In this study, we have established 3Y1 rat fibroblast cell lines that constitutively express SYT, SSX1, and SYT-SSX1 and found that ... SYT-SSX1 promoted growth rate in culture, anchorage-independent growth in soft agar, and tumor formation in nude mice. Deletion of the N-terminal 181 amino acids of SYT-SSX1 caused loss of its transforming activity. Furthermore, association of SYT-SSX1 with the chromatin remodeling factor hBRM/hSNF2 alpha, which regulates transcription, was demonstrated in both SYT-SSX1-expressing 3Y1 cells and in the human synovial sarcoma cell line HS-SY-II. The binding region between the two molecules was shown to reside within the N-terminal 181 amino acids stretch (aa 1--181) of SYT-SSX1 and 50 amino acids (aa 156--205) of hBRM/hSNF2 alpha and we found that the overexpression of this binding region of hBRM/hSNF2 alpha significantly suppressed the anchorage-independent growth of SYT-SSX1-expressing 3Y1 cells. To analyze the transcriptional regulation by SYT-SSX1, we established conditional expression system of SYT-SSX1 and examined the gene expression profiles. The down-regulation of potential tumor suppressor DCC was observed among 1,176 genes analyzed by microarray analysis, and semi-quantitative reverse transcription--PCR confirmed this finding. These data clearly demonstrate transforming activity of human oncogene SYT-SSX1 and also involvement of chromatin remodeling factor hBRM/hSNF2 alpha in human cancer.
Mesh Terms:
Agar, Animals, Cell Adhesion Molecules, Cell Line, Chromatin, DNA Helicases, DNA Mutational Analysis, DNA-Binding Proteins, Down-Regulation, Gene Expression Profiling, Gene Expression Regulation, Humans, Nuclear Proteins, Oncogene Proteins, Fusion, Rats, Receptors, Cell Surface, Sarcoma, Synovial, Transcription Factors, Tumor Cells, Cultured, Tumor Suppressor Proteins
Agar, Animals, Cell Adhesion Molecules, Cell Line, Chromatin, DNA Helicases, DNA Mutational Analysis, DNA-Binding Proteins, Down-Regulation, Gene Expression Profiling, Gene Expression Regulation, Humans, Nuclear Proteins, Oncogene Proteins, Fusion, Rats, Receptors, Cell Surface, Sarcoma, Synovial, Transcription Factors, Tumor Cells, Cultured, Tumor Suppressor Proteins
Proc. Natl. Acad. Sci. U.S.A.
Date: Mar. 27, 2001
PubMed ID: 11274403
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