Nur77 nuclear import and its NBRE-binding activity in thymic lymphoma cells are regulated by different mechanisms sensitive to FK506 or HA1004.
Thymic lymphoma cells restore their sensitivity to ionomycin-induced apoptosis when treated with FK506 or HA1004. In apoptosis-resistant cells, ionomycin-induced Nur77 strongly binds DNA during the first 2 h of response, in contrast to lymphoma cells treated with ionomycin together with FK506 or HA1004, which undergo massive apoptosis. We show that Nur77 could discriminate between calcium signals sensitive to FK506 and those sensitive to HA1004, as the inhibitors differentially regulate the kinetics of Nur77 nuclear import, and FK506, unlike HA1004, inhibits Nur77 DNA-binding activity. In the presence of HA1004, NBRE binding by Nur77 protein increases with time (6 h vs 2 h), whereas the final outcome of both inhibitors is apoptosis of thymic lymphoma cells.
Kochel
Izabela
I
Laboratory of Cellular and Molecular Immunology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114 Wroclaw, Poland.
Rapak
Andrzej
A
Ziolo
Ewa
E
Strzadala
Leon
L
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007546:Isoquinolines / Q000008:administration & dosage*; D008223:Lymphoma / Q000378:metabolism*; D051379:Mice; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D009841:Oligonucleotides / Q000378:metabolism*; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage*; D016559:Tacrolimus / Q000008:administration & dosage*; D013953:Thymus Neoplasms / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D007546:Isoquinolines; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D009841:Oligonucleotides; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013449:Sulfonamides; D014157:Transcription Factors; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D016559:Tacrolimus