A TFG-TEC nuclear localization mutant forms complexes with the wild-type TFG-TEC oncoprotein and suppresses its activity

초록

Human EMCs (extraskeletal myxoid chondrosarcomas) are soft tissue tumours characterized by specific chromosomal abnormalities. Recently, a proportion of EMCs were found to harbour a characteristic translocation, t(3;9)(q11-12;q22), involving the TFG (TRK-fused gene) at 3q11-12 and the TEC (translocated in extraskeletal chondrosarcoma) gene at 9q22. The present study used both in vitro and in vivo systems to show that the TFG TEC protein self-associates, and that this is dependent upon the CC (coiled-coil) domain (amino acids 97-124), the AF1 (activation function 1) domain (amino acids 275-562) and the DBD (DNA-binding domain) (amino acids 563-655). The TFG TEC protein also associated with a mutant NLS-TFG-TEC (AAAA) protein, which harbours mutations in the NLS (nuclear localization signal). Subcellular localization assays showed that the NLS mutant TFG TEC (AAAA) protein interfered with the nuclear localization of wild-type TFG TEC. Most importantly, the mutant protein inhibited TFG-TEC-mediated transcriptional activation in vivo. Thus mutations in the TFG TEC NLS yield a dominant-negative protein. These results show that the biological functions of the TFG-TEC oncogene can be modulated by a dominant-negative mutant.

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