Induction of a Secreted Protein by the Myxoid Liposarcoma Oncogene

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 9; pp. 5025 - 5030
• Main Authors: Kuroda, Masahiko, Wang, XiaoZhong, Sok, John, Yin Yin, Chung, Peter, Giannotti, JoAnn W., Jacobs, Kenneth A., Fitz, Lori J., Murtha-Riel, Patricia, Turner, Katherine J., Ron, David
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 27.04.1999; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Alleles; Animals; Biological Sciences; Cancer; CCAAT-Enhancer-Binding Proteins; Cells; Cells, Cultured; Cellular biology; CHO cells; Cloning, Molecular; Dimerization; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fibroblasts - metabolism; Gene Expression Regulation, Neoplastic; Genes; Humans; Liposarcoma; Liposarcoma, Myxoid - genetics; Liposarcoma, Myxoid - metabolism; Mice; Molecular Sequence Data; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nuclear Proteins - genetics; Oncogene Proteins, Fusion - genetics; Proteins; RNA-Binding Protein FUS; Stem cells; Transcription Factor CHOP; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.9.5025

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 expression 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.