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J Biol Chem, Vol. 274, Issue 51, 36125-36131, December 17, 1999
,¶
From the Departments of Calcineurin, a
Ca2+/calmodulin-stimulated protein phosphatase, plays
a key role in T-cell activation by regulating the activity of NFAT
(nuclear factor of activated
T cells), a family of transcription factors required for
the synthesis of several cytokine genes. Calcineurin is the target of
the immunosuppressive drugs cyclosporin A and FK506 complexed with
their cytoplasmic receptors cyclophilin and FKBP12, respectively. In
this study we report that calcineurin is also the target of a recently
identified Ca2+-binding protein, CHP (for
calcineurin homologous protein),
which shares a high degree of homology with the regulatory B subunit of
calcineurin and with calmodulin. In Jurkat and HeLa cells, overexpression of CHP specifically impaired the nuclear translocation and transcriptional activity of NFAT but had no effect on AP-1 transcriptional activity and only a small (<25%) inhibitory effect on
the transcriptional activity of NF Stomatology and
¶ Surgery, University of California, San Francisco, California
94143 and the § Section of Hematology Research and the
Department of Biochemistry and Molecular Biology, Mayo Clinic and
Foundation, Rochester, Minnesota 55905
B. Further study indicated that
CHP inhibits calcineurin activity. In cells overexpressing CHP, the
phosphatase activity of immunoprecipitated calcineurin was inhibited by
~50%; and in a reconstituted assay, the activity of purified
calcineurin was inhibited up to 97% by the addition of purified
recombinant CHP in a dose-dependent manner. Moreover, prolonged activation of Jurkat cells was associated with a decreased abundance of CHP, suggesting a possible regulatory mechanism allowing activation of calcineurin. CHP, therefore, is a previously unrecognized endogenous inhibitor of calcineurin activity.
Is an Established Investigator for the American Heart
Association. To whom correspondence should be addressed: Box 0512, HSW 604, University of California, San Francisco, CA 94143-0512. Tel.: (415) 476-3764; Fax: (415) 502-7338; E-mail:
barber@itsa.ucsf.edu.
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