Induction of a secreted protein by the myxoid liposarcoma oncogene

The TLS-CHOP oncoprotein, found in the majority of human myxoid liposarcoma s, consists of a fusion between the transcription factor CHOP/GADD153 and t he N terminus of an RNA-binding protein TLS/FUS, Clinical correlation and i ll vitro transformation assays indicate that the N terminus of TLS plays an important role in oncogenesis by TLS-CHOP, Until now, however, the only ac tivity attributed to the oncoprotein is that of inhibiting the binding of t ranscription factors of the C/EBP class to certain adipogenic target genes, a function that TLS CHOP shares with the nononcogenic CHOP protein. Here w e report the isolation of a gene, DOL54, that is activated in primary fibro blasts 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-bin ding and dimerization domain in TLS-CHOP, a suitable cellular dimerization partner, and depends on the TLS N terminus. Normal adipocytic differentiati on is associated with an early and transient expression of DOL54, and the g ene encodes a secreted protein that is tightly associated with the cell sur face or extracellular matrix. TLS-CHOP thus leads to the unscheduled expres sion of a gene that is normally associated with adipocytic differentiation.