Functional interaction of the immunosuppressant mizoribine with the 14-3-3 protein.
Mizoribine (MIZ) is a novel imidazole nucleoside with immunosuppressive activity. MIZ has been approved in Japan and combination therapy with MIZ and glucocorticoids has been used after renal transplantation and for lupus nephritis and rheumatoid arthritis. In this study, we identify 14-3-3 proteins as MIZ-binding proteins. 14-3-3 proteins interact with many proteins involved in cellular signaling, including the glucocorticoid receptor (GR). The 14-3-3/GR interaction enhances the transcriptional activity of the receptor. We show that MIZ affects the conformation of 14-3-3 proteins and enhances the interaction of GR and 14-3-3eta dose dependently in vitro. MIZ also has a stimulatory effect on transcriptional activation by the GR. Our results point to the possibility that one mechanism for the therapeutic effect of MIZ could be to regulate the GR function via 14-3-3 proteins.
Takahashi
S
S
Department of Medical Nutrition, Karolinska Institutet, Novum, Huddinge, S-141 86, Sweden.
Wakui
H
H
Gustafsson
J A
JA
Zilliacus
J
J
Itoh
H
H
D048948:14-3-3 Proteins; D000818:Animals; D019556:COS Cells; D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005982:Glutathione Transferase / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D007668:Kidney / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012263:Ribonucleosides / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction; D013053:Spectrophotometry; D013552:Swine; D015533:Transcriptional Activation; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase
D048948:14-3-3 Proteins; D007166:Immunosuppressive Agents; D011506:Proteins; D011965:Receptors, Glucocorticoid; D012263:Ribonucleosides; C010052:mizoribine; D014446:Tyrosine 3-Monooxygenase; D005982:Glutathione Transferase