The FKBP-associated protein FAP48 is an antiproliferative molecule and a player in T cell activation that increases IL2 synthesis.
FAP48 was identified and cloned thanks to its interaction with FK506-binding proteins (FKBPs) such as FKBP52 and FKBP12, which belong to the large family of immunophilins that bind the macrolide immunosuppressant drugs FK506 and rapamycin. We have previously shown that FAP48-FKBP complexes are dissociated by FK506 and rapamycin, suggesting that FAP48 is an endogenous ligand of FKBP. The present work describes the biochemical consequences of FAP48 overexpression, induced by the tetracycline analogue doxycycline, in an established cell line derived from Jurkat T cells. We report that overexpression of FAP48 results in the inhibition of cellular proliferation as does the exposure of Jurkat T cells to FK506. We also show that the expression levels of argininosuccinate synthetase and the Myc antagonist Mxi1 are modified by overexpression of FAP48, suggesting that these proteins could be good candidates to mediate the antiproliferative effect of FAP48. FAP48 affects neither the calcineurin-dependent nuclear factor of activated T cells (NFAT)1 nor JNKp38-dependent pathways that mediate immunosuppression by FK506. However, contrary to FK506, which blocks IL2 synthesis, we observed that FAP48-FKBP complexes increase IL2 production, thus revealing a previously uncharacterized aspect of the immunosuppressive mechanism of FK506.
Krummrei
Ulrike
U
Institut National de la Santé et de la Recherche Médicale, Unité 488, 80 Rue du Général Leclerc, 94276 Bicêtre Cedex, France.
Baulieu
Etienne-Emile
EE
Chambraud
Béatrice
B
D048868:Adaptor Proteins, Signal Transducing; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins; D002455:Cell Division / Q000187:drug effects; D002469:Cell Separation; D003001:Cloning, Molecular; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004318:Doxycycline / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism*; D019169:Jurkat Cells; D008024:Ligands; D008954:Models, Biological; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011233:Precipitin Tests; D011485:Protein Binding; D013601:T-Lymphocytes / Q000166:cytology*; D022021:Tacrolimus Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; D000900:Anti-Bacterial Agents; D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D004268:DNA-Binding Proteins; D004318:Doxycycline; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D008024:Ligands; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D022021:Tacrolimus Binding Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C103024:GLMN protein, human; C079440:MXI1 protein, human; C403485:tacrolimus binding protein 4