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Abstract

Calcineurin mutants render T lymphocytes resistant to cyclosporin A.

D Zhu, M E Cardenas and J Heitman
Molecular Pharmacology September 1996, 50 (3) 506-511;
D Zhu
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M E Cardenas
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J Heitman
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Abstract

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.

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Molecular Pharmacology
Vol. 50, Issue 3
1 Sep 1996
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Abstract

Calcineurin mutants render T lymphocytes resistant to cyclosporin A.

D Zhu, M E Cardenas and J Heitman
Molecular Pharmacology September 1, 1996, 50 (3) 506-511;

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Abstract

Calcineurin mutants render T lymphocytes resistant to cyclosporin A.

D Zhu, M E Cardenas and J Heitman
Molecular Pharmacology September 1, 1996, 50 (3) 506-511;
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