Abstract:
:The immunosuppressive drugs FK506 and rapamycin bind to a family of intracellular proteins termed FK506-binding proteins (FKBP). FK506 and rapamycin inhibit lymphocyte-activation pathways by forming complexes with an FKBP; subsequently, the drug/FKBP complexes interact with target molecules involved in signal transduction. A key target of FK506/FKBP12 complexes is calcineurin, a calcium- and calmodulin-dependent serine/threonine phosphatase. In mammalian cells, rapamycin treatment is associated with inhibition of the activity of several cellular serine/threonine kinases, including p70 S6 kinase. These kinases may function in signaling pathways involving TOR gene producs, which have been shown to interact with rapamycin/FKBP12 complexes in vitro. To determine if FKBP12 mediates the effects of both FK506 and rapamycin in mammalian cells, we overexpressed FKBP12 in a murine mast cell line. Increased expression of FKBP12 resulted in increased sensitivity to FK506 and rapamycin, as measured by inhibition of calcineurin activity and p70 S6 kinase activity, respectively. In contrast, overexpression of FKBP25 had no effect on sensitivity to either drug. Two distinct point mutations in FKBP12, one altering a hydrophobic residue within the drug-binding pocket and the other changing a charged surface residue of FKBP12, abrogated its ability to mediate sensitivity to FK506 and rapamycin. These results establish that FKBP12 can mediate sensitivity to both FK506 and rapamycin in mammalian cells.
journal_name
Eur J Immunoljournal_title
European journal of immunologyauthors
Fruman DA,Wood MA,Gjertson CK,Katz HR,Burakoff SJ,Bierer BEdoi
10.1002/eji.1830250239subject
Has Abstractpub_date
1995-02-01 00:00:00pages
563-71issue
2eissn
0014-2980issn
1521-4141journal_volume
25pub_type
杂志文章abstract::This study was conducted to further characterize the effector cells of experimental allergic encephalomyelitis (EAE) which are activated in vitro when spleen cells from Lewis rats previously immunized with myelin basic protein and adjuvant are cultured with antigen prior to transfer to syngeneic recipients. The effect...
journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/eji.1830120519
更新日期:1982-05-01 00:00:00
abstract::In this study we have examined the role of small numbers of adherent cells in the stimulation of highly purified resting T lymphocytes by cross-linked monoclonal anti-CD3 antibodies (T3). T cells were obtained by 3 cycles of purification, using adherence to plastic surface, nylon wool column separation and rosetting w...
journal_title:European journal of immunology
pub_type: 杂志文章
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journal_title:European journal of immunology
pub_type: 杂志文章
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更新日期:1994-06-01 00:00:00
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journal_title:European journal of immunology
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更新日期:2014-12-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
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更新日期:1993-01-01 00:00:00
abstract::Adoptive T-cell therapy (ATCT) can result in tumor rejection, yet the behavior and fate of the introduced T cells remain unclear. We developed a novel bioluminescence mouse model, which enabled highly sensitive detection of T-cell signals at the single-cell level. Transferred T cells preferentially accumulated within ...
journal_title:European journal of immunology
pub_type: 杂志文章
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更新日期:2011-11-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/eji.201142010
更新日期:2012-01-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/eji.1830210636
更新日期:1991-06-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
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更新日期:1994-08-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章,评审
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更新日期:2006-11-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/eji.1830141011
更新日期:1984-10-01 00:00:00
abstract::Studies of experimental autoimmune encephalomyelitis (EAE) in rodents have revealed that encephalitogenic T cell lines reactive with myelin basic protein (BP) are frequently dominated by clones expressing a restricted T cell receptor repertoire. Using the rat EAE model, we have begun to examine the basis for clonal do...
journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/eji.1830250114
更新日期:1995-01-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/eji.1830190630
更新日期:1989-06-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/eji.1830251230
更新日期:1995-12-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/eji.200838801
更新日期:2009-02-01 00:00:00
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pub_type: 杂志文章
doi:10.1002/1521-4141(200105)31:5<1438::AID-IMMU1438>3
更新日期:2001-05-01 00:00:00
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journal_title:European journal of immunology
pub_type: 评论,杂志文章
doi:10.1002/eji.201747249
更新日期:2017-11-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/(SICI)1521-4141(199805)28:05<1636::AID-IMM
更新日期:1998-05-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
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更新日期:1999-01-01 00:00:00
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journal_title:European journal of immunology
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journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/eji.1830250704
更新日期:1995-07-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/eji.1830210304
更新日期:1991-03-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/eji.1830220111
更新日期:1992-01-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
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更新日期:1999-12-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
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更新日期:1996-03-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
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更新日期:1982-11-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/eji.1830140203
更新日期:1984-02-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/1521-4141(200012)30:12<3672::AID-IMMU3672>
更新日期:2000-12-01 00:00:00