Induction of a secreted protein by the myxoid liposarcoma oncogene

Masahiko Kuroda, Xiao Zhong Wang, John Sok, Yin Yin, Peter Chung, Jo Ann W Giannotti, Kenneth A. Jacobs, Lori J. Fitz, Patricia Murtha-Riel, Katherine J. Turner, David Ron*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

The TLS-CHOP oncoprotein, found in the majority of human myxoid liposarcomas, consists of a fusion between the transcription factor CHOP/GADD153 and the N terminus of an RNA-binding protein TLS/FUS. Clinical correlation and in vitro transformation assays indicate that the N terminus of TLS plays an important role in oncogenesis by TLS-CHOP. Until now, however, the only activity attributed to the oncoprotein is that of inhibiting the binding of transcription factors of the C/EBP class to certain adipogenic target genes, a function that TLS-CHOP shares with the nononcogenic CHOP protein. Here we report the isolation of a gene, DOL54, that is activated in primary fibroblasts by the ex, pression of TLS-CHOP. DOL54 is expressed in the neoplastic component of human myxoid liposarcomas and increases the tumorigenicity of cells injected in nude mice. Activation of DOL54 requires an intact DNA-binding and dimerization domain in TLS-CHOP, a suitable cellular dimerization partner, and depends on the TLS N terminus. Normal adipocytic differentiation is associated with an early and transient expression of DOL54, and the gene encodes a secreted protein that is tightly associated with the cell surface or extracellular matrix. TLS-CHOP thus leads to the unscheduled expression of a gene that is normally associated with adipocytic differentiation.

Original languageEnglish (US)
Pages (from-to)5025-5030
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number9
DOIs
StatePublished - Apr 27 1999

ASJC Scopus subject areas

  • General

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