Publication Date:
1999-09-25
Description:
The flow of information from calcium-mobilizing receptors to nuclear factor of activated T cells (NFAT)-dependent genes is critically dependent on interaction between the phosphatase calcineurin and the transcription factor NFAT. A high-affinity calcineurin-binding peptide was selected from combinatorial peptide libraries based on the calcineurin docking motif of NFAT. This peptide potently inhibited NFAT activation and NFAT-dependent expression of endogenous cytokine genes in T cells, without affecting the expression of other cytokines that require calcineurin but not NFAT. Substitution of the optimized peptide sequence into the natural calcineurin docking site increased the calcineurin responsiveness of NFAT. Compounds that interfere selectively with the calcineurin-NFAT interaction without affecting calcineurin phosphatase activity may be useful as therapeutic agents that are less toxic than current drugs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Aramburu, J -- Yaffe, M B -- Lopez-Rodriguez, C -- Cantley, L C -- Hogan, P G -- Rao, A -- R01 AI 40127/AI/NIAID NIH HHS/ -- R01 GM056203/GM/NIGMS NIH HHS/ -- R01 HL 03601/HL/NHLBI NIH HHS/ -- R43 AI 43726/AI/NIAID NIH HHS/ -- etc. -- New York, N.Y. -- Science. 1999 Sep 24;285(5436):2129-33.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10497131" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Binding Sites
;
Calcineurin/*metabolism
;
Calcineurin Inhibitors
;
Cell Nucleus/metabolism
;
Cyclosporine/pharmacology
;
Cytokines/biosynthesis/genetics
;
DNA-Binding Proteins/*antagonists & inhibitors/chemistry/metabolism
;
Gene Expression Regulation
;
Genes, Reporter
;
HeLa Cells
;
Humans
;
Immunosuppressive Agents/chemistry/metabolism/*pharmacology
;
Jurkat Cells
;
Molecular Sequence Data
;
NFATC Transcription Factors
;
*Nuclear Proteins
;
Oligopeptides/chemistry/metabolism/*pharmacology
;
Peptide Library
;
Peptides/chemistry/metabolism/*pharmacology
;
Phosphorylation
;
Recombinant Fusion Proteins/metabolism
;
T-Lymphocytes/*drug effects/immunology
;
Transcription Factors/*antagonists & inhibitors/chemistry/metabolism
;
Transfection
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
