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 development of red blood cells. We have shown previously that the tyrosine kinase Lyn is involved in differentiation signals emanating from an activated erythropoietin receptor. Here we demonstrate that Lyn interacts with thyroid hormone receptor-interacting protein 1 (Trip-1), a transcriptional regulator 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 alpha in the cytoplasm/plasma membrane of erythroid cells but translocated to 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. Strikingly, a truncated Trip-1 inhibited both erythropoietin-induced maturation and T(3)-initiated cell division. This mutant Trip-1 acted in a dominant negative fashion by eliminating endogenous Lyn, elevating p27(Kip1), and blocking T(3) response elements. These data demonstrate that Trip-1 can simultaneously modulate responses involving both cytokine and nuclear receptors.
Ingley
E
E
Laboratory for Cancer Medicine, Western Australian Institute for Medical Research, Royal Perth Hospital and the Department of Biochemistry, University of Western Australia, Perth, Western Australia 6000, Australia.
Chappell
D
D
Poon
S Y
SY
Sarna
M K
MK
Beaumont
J G
JG
Williams
J H
JH
Stillitano
J P
JP
Tsai
S
S
Leedman
P J
PJ
Tilbrook
P A
PA
Klinken
S P
SP
D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004912:Erythrocytes / Q000378:metabolism; D050981:Erythroid-Specific DNA-Binding Factors; D019084:Fluorescent Antibody Technique, Indirect; D050982:GATA1 Transcription Factor; D015151:Immunoblotting; D051741:Kruppel-Like Transcription Factors; D060588:LIM Domain Proteins; D051379:Mice; D050983:NF-E2 Transcription Factor; D050984:NF-E2 Transcription Factor, p45 Subunit; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D012190:Retroviridae / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D019061:src-Family Kinases / Q000096:biosynthesis
D048868:Adaptor Proteins, Signal Transducing; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D060588:LIM Domain Proteins; D050983:NF-E2 Transcription Factor; D050984:NF-E2 Transcription Factor, p45 Subunit; C494693:Nfe2 protein, mouse; C092282:PSMC5 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C080774:erythroid Kruppel-like factor; D050760:Cyclin-Dependent Kinase Inhibitor p27; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities