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PMID: 7515500 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Calcineurin is essential in cyclosporin A- and FK506-sensitive yeast strains.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 91 ·No. 12 ·1994-06-07 ·Pages 5372-6

Breuder T, Hemenway CS, Movva NR, Cardenas ME, Heitman J

Abstract

The immunophilin-immunosuppressant complexes cyclophilin-cyclosporin A (CsA) and FKBP12-FK506 inhibit the phosphatase calcineurin to block T-cell activation. Although cyclophilin A, FKBP12, and calcineurin are highly conserved from yeast to man, none had previously been shown to be essential for viability. We find that CsA-sensitive yeast strains are FK506 hypersensitive and demonstrate that calcineurin is required for viability in these strains. Mutants lacking cyclophilin A or FKBP12 are resistant to CsA or FK506, respectively. Thus, both the immunosuppressive and the antifungal actions of CsA and FK506 result from calcineurin inhibition by immunophilin-drug complexes. In yeast strains in which calcineurin is not essential, calcineurin inhibition or mutation of calcineurin confers hypersensitivity to LiCl or NaCl, suggesting that calcineurin regulates cation transport.

Related Genes
CPR1
MeSH Terms
Amino Acid Isomerases/pharmacology Base Sequence Calcineurin Calmodulin-Binding Proteins/antagonists & inhibitors,physiology Carrier Proteins/pharmacology Cyclosporine/toxicity DNA Primers/chemistry Drug Resistance, Microbial Lithium/pharmacology Molecular Sequence Data Neomycin/pharmacology Peptidylprolyl Isomerase Phosphoprotein Phosphatases/antagonists & inhibitors,physiology Saccharomyces cerevisiae/drug effects Sodium/pharmacology Tacrolimus/analogs & derivatives,toxicity
Chemicals
Calmodulin-Binding Proteins Carrier Proteins DNA Primers Cyclosporine Lithium Sodium immunomycin Calcineurin Phosphoprotein Phosphatases Amino Acid Isomerases Peptidylprolyl Isomerase Neomycin Tacrolimus
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Breuder T
Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710.
Hemenway C S
Movva N R
Cardenas M E
Heitman J
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.91.12.5372
Published
1994-06-07
Pages
5372-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC43997
Subset
IM
Grants
NIEHS NIH HHS · ES07031 · United States
External Links
PubMed source DOI: 10.1073/pnas.91.12.5372 PMC Full Text View journal details
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