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Calcineurin acts in synergy with PMA to inactivate I kappa B/MAD3, an inhibitor of NF‐kappa B.
Author(s) -
Frantz B.,
Nordby E.C.,
Bren G.,
Steffan N.,
Paya C.V.,
Kincaid R.L.,
Tocci M.J.,
O'Keefe S.J.,
O'Neill E.A.
Publication year - 1994
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1002/j.1460-2075.1994.tb06329.x
Subject(s) - library science , computer science
The interleukin‐2 (IL‐2) promoter consists of several independent T cell receptor (TcR) responsive elements. The induction of promoters dependent on these elements is inhibitable by the immunosuppressants cyclosporin A (CsA) and tacrolimus (FK‐506). Calcineurin, a Ca2+/calmodulin‐dependent protein phosphatase, is the FK‐506‐ and CsA‐sensitive enzyme required for TcR mediated activation of the IL‐2 promoter. We report that a constitutively active form of calcineurin partially substitutes for the Ca2+ co‐stimulus required to activate the IL‐2 promoter elements IL‐2A (which binds the factors OAP and Oct‐1) and IL‐2E (which binds NF‐AT), and completely substitutes for the Ca2+ co‐stimulus required to stimulate an NF‐kappa B‐dependent element. Calcineurin stimulates the NF‐kappa B element by enhancing inactivation of I kappa B/MAD3, an inhibitor of NF‐kappa B, thereby increasing the amount of nuclear NF‐kappa B DNA binding activity. These data provide the first demonstration in vivo that activation of a protein phosphatase can inactivate I kappa B, and suggest one possible explanation for mechanism‐based toxicities associated with FK‐506 and CsA by demonstrating that these drugs can inhibit the calcineurin‐dependent activation of a virtually ubiquitous transcription factor.