Thyroid hormone receptor-interacting protein 1 modulates cytokine and nuclear hormone signaling in erythroid cells

Erythropoietin (Epo) and thyroid hormone (T-3) are key molecules in the dev elopment of red blood cells. We have shown previously that the tyrosine kin ase Lyn is involved in differentiation signals emanating from an activated erythropoietin receptor. Here we demonstrate that Lyn interacts with thyroi d hormone receptor-interacting protein 1 (Trip-1), a transcriptional regula tor associated with the T-3 receptor, providing a link between the Epo and T-3 signaling pathways. Trip-1 co-localized with Lyn and the T-3 receptor a lpha in the cytoplasm/plasma membrane of erythroid cells but translocated t o discrete nuclear foci shortly after Epo-induced differentiation. Our data reveal that T-3 stimulated the proliferation of immature erythroid cells, and inhibited maturation promoted by erythropoietin. Removal of T-3 reduced cell division and enhanced terminal differentiation. This was accompanied by large increases in the cell cycle inhibitor P27(Kip1) and by increasing expression of erythroid transcription factors GATA-1, EKLF, and NF-E2. Stri kingly, a truncated Trip-1 inhibited both erythropoietin-induced maturation and T-3-initiated cell division. This mutant Trip-1 acted in a dominant ne gative fashion by eliminating endogenous Lyn, elevating p27(Kip1), and bloc king T-3 response elements. These data demonstrate that Trip-1 can simultan eously modulate responses involving both cytokine and nuclear receptors.