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SYT-SSX is critical for cyclin D1 expression in synovial sarcoma cells: A gain of function of the t(X;18)(p11.2;q11.2) translocation

Author

  • YT Xie
  • B Skytting
  • G Nilsson
  • A Gasbarri
  • K Haslam
  • A Bartolazzi
  • B Brodin
  • Nils Mandahl
  • O Larsson

Summary, in English

The SYT-SSX fusion gene has been implicated in the malignant tumor cell growth of synovial sarcoma, but the underlying molecular mechanisms are still poorly understood. Here we demonstrate that SYT-SSX is critical for the protein level of cyclin D1 in synovial sarcoma cells. Antisense oligonucleotides to SYT-SSX mRNA rapidly and drastically decreased cyclin D1 and subsequently inhibited cell growth. This effect is specific for SYT-SSX, without involving the wild-type genes SYT or SSX. The decrease in cyclin D1 expression, which occurred shortly after inhibition of SYT-SSX expression, was found to be primarily dependent on an increased degradation of the cyclin D1 protein, as assessed by pulse-chase experiments using [S-35]methionine. Furthermore, transfection of mouse fibroblasts with SYT-SSX cDNA increased the stability of cyclin D1. Because treatment with a proteasome inhibitor restored cyclin D1 expression, it seems like SYT-SSX interferes with ubiquitin-dependent degradation of cyclin D1. However, SYT-SSX-regulated cyclin D1 expression was proven to be independent of the glycogen synthetase kinase-3beta pathway. Taken together, our study provides evidence that SYT-SSX stabilizes cyclin D1 and is critical for cyclin D1 expression in synovial sarcoma cells. SYT-SSX-dependent expression of cyclin D1 may be an important mechanism in the development and progression of synovial sarcoma and also raises the possibility for targeted therapy.

Publishing year

2002

Language

English

Pages

3861-3867

Publication/Series

Cancer Research

Volume

62

Issue

13

Document type

Journal article

Publisher

American Association for Cancer Research Inc.

Topic

  • Medical Genetics

Status

Published

ISBN/ISSN/Other

  • ISSN: 1538-7445