RAPAMYCIN SELECTIVELY INHIBITS INTERLEUKIN-2 ACTIVATION OF P70 S6 KINASE

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THE macrolide rapamycin induces cell cycle G1 arrest in yeast and in mammalian cells 1-3, which suggests that an evolutionarily conserved, rapamycin-sensitive pathway may regulate entry into S phase. In mammals, rapamycin inhibits interleukin-2 receptor-induced S phase entry and subsequent T-cell proliferation 4-6, resulting in immunosuppression. Here we show that interleukin-2 selectively stimulates the phosphorylation and activation of p70 S6 kinase but not the erk-encoded MAP kinases and rsk-encoded S6 kinases 7,8. Rapamycin completely and rapidly inhibits interleukin-2-induced phosphorylation and activation of p70 S6 kinase at concentrations comparable to those blocking S phase entry of T cells (0.05-0.2 nM). The structurally related macrolide FK506 competitively antagonizes the actions of rapamycin, indicating that these effects are mediated by FKBP, which binds the transition-state mimic structure common to both rapamycin and FK506 (refs 4, 6, 9-11). The selective blockade of the p70 S6 kinase activation cascade by the rapamycin-FKBP complex implicates this signalling pathway in the regulation of T cell entry into S phase.
Publisher
MACMILLAN MAGAZINES LTD
Issue Date
1992-07
Language
English
Article Type
Article
Keywords

PEPTIDYL-PROLYL ISOMERASE; IMMUNOSUPPRESSANT FK506; MACROLIDES FK-506; DISTINCT; PROTEIN; CLONING; ENZYME; CELLS

Citation

NATURE, v.358, no.6381, pp.70 - 73

ISSN
0028-0836
DOI
10.1038/358070a0
URI
http://hdl.handle.net/10203/60568
Appears in Collection
BS-Journal Papers(저널논문)
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