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Calcineurin mutants render T lymphocytes resistant to cyclosporin A.

Publication ,  Journal Article
Zhu, D; Cardenas, ME; Heitman, J
Published in: Mol Pharmacol
September 1996

The immunosuppressants cyclosporin A (CsA) and FK506 have been widely used to prevent and treat graft rejection after human organ and tissue transplantations. CsA and FK506 associate with intracellular binding proteins (i.e., CsA with cyclophilin A and FK506 with FKBP12) to form protein/drug complexes that suppress the immune system by preventing activation of T cells in response to antigen presentation. The common target of CsA and FK506 is calcineurin, a Ca2+/calmodulin-regulated, serine/threonine-specific protein phosphatase that regulates the nuclear import of a transcription factor, NF-AT, required for expression of T cell activation genes. In previous studies, we identified calcineurin mutations that block binding by the cyclophilin A/CsA or FKBP12/FK506 complexes and thereby render yeast cells resistant to the antifungal effects of CsA or FK506. In this report, we demonstrate that the corresponding mutations in murine calcineurin render the T cell receptor signal transduction cascade CsA resistant in human Jurkat T cells. Our findings support the recently determined calcineurin X-ray crystal structure, provide evidence that calcineurin is the only CsA-sensitive component limiting signaling from the T cell receptor to the nucleus, and suggest a means to render cells and tissues resistant to the toxic side effects of CsA and FK506.

Duke Scholars

Published In

Mol Pharmacol

ISSN

0026-895X

Publication Date

September 1996

Volume

50

Issue

3

Start / End Page

506 / 511

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transfection
  • Transcription Factors
  • T-Lymphocytes
  • Simian virus 40
  • Signal Transduction
  • Sequence Homology, Amino Acid
  • Recombinant Proteins
  • Polymerase Chain Reaction
  • Phosphoprotein Phosphatases
 

Citation

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Zhu, D., Cardenas, M. E., & Heitman, J. (1996). Calcineurin mutants render T lymphocytes resistant to cyclosporin A. Mol Pharmacol, 50(3), 506–511.
Zhu, D., M. E. Cardenas, and J. Heitman. “Calcineurin mutants render T lymphocytes resistant to cyclosporin A.Mol Pharmacol 50, no. 3 (September 1996): 506–11.
Zhu D, Cardenas ME, Heitman J. Calcineurin mutants render T lymphocytes resistant to cyclosporin A. Mol Pharmacol. 1996 Sep;50(3):506–11.
Zhu, D., et al. “Calcineurin mutants render T lymphocytes resistant to cyclosporin A.Mol Pharmacol, vol. 50, no. 3, Sept. 1996, pp. 506–11.
Zhu D, Cardenas ME, Heitman J. Calcineurin mutants render T lymphocytes resistant to cyclosporin A. Mol Pharmacol. 1996 Sep;50(3):506–511.

Published In

Mol Pharmacol

ISSN

0026-895X

Publication Date

September 1996

Volume

50

Issue

3

Start / End Page

506 / 511

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transfection
  • Transcription Factors
  • T-Lymphocytes
  • Simian virus 40
  • Signal Transduction
  • Sequence Homology, Amino Acid
  • Recombinant Proteins
  • Polymerase Chain Reaction
  • Phosphoprotein Phosphatases