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PMID: 8112299 Published · ppublish English Journal Article

Calcineurin acts in synergy with PMA to inactivate I kappa B/MAD3, an inhibitor of NF-kappa B.

The EMBO journal ·Vol. 13 ·No. 4 ·1994-02-15 ·Pages 861-70

Frantz B, Nordby EC, Bren G, Steffan N, Paya CV, Kincaid RL, Tocci MJ, O'Keefe SJ, O'Neill EA

Abstract

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.

MeSH Terms
Base Sequence Calcineurin Calmodulin-Binding Proteins/pharmacology Cells, Cultured DNA/metabolism DNA-Binding Proteins/antagonists & inhibitors Drug Synergism Humans I-kappa B Proteins Molecular Sequence Data NF-KappaB Inhibitor alpha NF-kappa B/antagonists & inhibitors Oligodeoxyribonucleotides Phosphoprotein Phosphatases/pharmacology Proto-Oncogene Proteins/antagonists & inhibitors T-Lymphocytes/drug effects,metabolism Tetradecanoylphorbol Acetate/pharmacology Transcription Factor RelB Transcription Factors/antagonists & inhibitors
Chemicals
Calmodulin-Binding Proteins DNA-Binding Proteins I-kappa B Proteins NF-kappa B NFKBIA protein, human Oligodeoxyribonucleotides Proto-Oncogene Proteins RELB protein, human Transcription Factors NF-KappaB Inhibitor alpha Transcription Factor RelB DNA Calcineurin Phosphoprotein Phosphatases Tetradecanoylphorbol Acetate
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Frantz B
Department of Molecular Immunology, Merck Research Laboratories, Rahway, NJ 07065.
Nordby E C
Bren G
Steffan N
Paya C V
Kincaid R L
Tocci M J
O'Keefe S J
O'Neill E A
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1994-02-15
Pages
861-70
Language
English
Region
England
NLM ID
8208664
PMCID
PMC394885
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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