PMID- 10593895
OWN - NLM
STAT- MEDLINE
DCOM- 20000127
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 51
DP  - 1999 Dec 17
TI  - Inhibition of calcineurin phosphatase activity by a calcineurin B homologous
      protein.
PG  - 36125-31
AB  - Calcineurin, a Ca(2+)/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 Ca(2+)-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 NFkappaB. Further study indicated that CHP inhibits calcineurin
      activity. In cells overexpressing CHP, the phosphatase activity of
      immunoprecipitated calcineurin was inhibited by approximately 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.
FAU - Lin, X
AU  - Lin X
AD  - Department of Stomatology, University of California, San Francisco, California
      94143, USA.
FAU - Sikkink, R A
AU  - Sikkink RA
FAU - Rusnak, F
AU  - Rusnak F
FAU - Barber, D L
AU  - Barber DL
LA  - eng
GR  - DK40259/DK/NIDDK NIH HHS/United States
GR  - GM 47413/GM/NIGMS NIH HHS/United States
GR  - GM46865/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Calcium-Binding Proteins)
RN  - EC 3.1.3.- (calcineurin phosphatase)
RN  - EC 3.1.3.16 (Calcineurin)
RN  - EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
SB  - IM
MH  - Calcineurin/genetics/*pharmacology
MH  - Calcium-Binding Proteins/genetics/*pharmacology
MH  - Enzyme Activation/drug effects
MH  - Humans
MH  - Jurkat Cells
MH  - Lymphocyte Activation/drug effects
MH  - Phosphoric Monoester Hydrolases/*antagonists & inhibitors
MH  - T-Lymphocytes/metabolism
MH  - Transfection
EDAT- 1999/12/14 00:00
MHDA- 1999/12/14 00:01
CRDT- 1999/12/14 00:00
PHST- 1999/12/14 00:00 [pubmed]
PHST- 1999/12/14 00:01 [medline]
PHST- 1999/12/14 00:00 [entrez]
AID - 10.1074/jbc.274.51.36125 [doi]
AID - S0021-9258(19)53139-8 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Dec 17;274(51):36125-31. doi: 10.1074/jbc.274.51.36125.