TLS (TRANSLOCATED-IN-LIPOSARCOMA) IS A HIGH-AFFINITY INTERACTOR FOR STEROID, THYROID-HORMONE, AND RETINOID RECEPTORS

Nuclear receptors for steroid hormones, thyroid hormone, retinoids, an d vitamin D are thought to mediate their transcriptional effects in co ncert with coregulator proteins that modulate receptor interactions wi th components of the basal transcription complex. In an effort to iden tify potential coregulators, receptor fusions with glutathione-S-trans ferase were used to isolate proteins in nuclear extracts capable of bi nding nuclear hormone receptors. Glutathione-S-transferase fusions wit h mouse retinoid X receptor-alpha enabled the selective isolation of a 65-kDa protein (p65) from nuclear extracts of rat and human cells. Bi nding of p65 to mouse retinoid X receptor-alpha was centered around th e DNA-binding domain. p65 also bound regions encompassing the DNA-bind ing domain in estrogen, thyroid hormone, and glucocorticoid receptors. p65 was identified as TLS (translocated-in-liposarcoma), a recently i dentified member of the RNP family of nuclear RNA-binding proteins who se members are thought to function in RNA processing. The N-terminal h alf of TLS bound to thyroid hormone receptor with high affinity while the receptor was bound to appropriate DNA target sites. Functional stu dies indicated that the N-terminal half of TLS can interact with thyro id hormone receptor in vivo. TLS was originally discovered as part of a fusion protein arising from a chromosomal translocation causing huma n myxoid liposarcomas. TLS contains a potent transactivation domain wh ose translocation-induced fusion with a DNA-binding protein (CHOP) yie lds a powerful transforming oncogene and transcription factor. The tra nsactivation and RNA-binding properties of TLS and the nature of its i nteraction with nuclear receptors suggest a novel role in nuclear rece ptor function.