| Fas apoptosis inhibitory molecule regulates T cell receptor-mediated apoptosis of thymocytes by modulating Akt activation and Nur77 expression. | |
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MedLine Citation:
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PMID: 20178987 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Fas apoptosis inhibitory molecule (FAIM) has been demonstrated to confer resistance to Fas-induced apoptosis of lymphocytes and hepatocytes in vitro and in vivo. Here, we show that FAIM is up-regulated in thymocytes upon T cell receptor (TCR) engagement and that faim(-/-) thymocytes are highly susceptible to TCR-mediated apoptosis with increased activation of caspase-8 and -9. Furthermore, injection of anti-CD3 antibodies leads to augmented depletion of CD4(+)CD8(+) T cells in the thymus of faim(-/-) mice compared with wild-type control, suggesting that FAIM plays a role in thymocyte apoptosis. Cross-linking of the TCR on faim(-/-) thymocytes leads to an elevated protein level of the orphan nuclear receptor Nur77, which plays a role in thymocyte apoptosis. Interestingly, in the absence of FAIM, there are reduced ubiquitination and degradation of the Nur77 protein. Faim(-/-) thymocytes also exhibit a defective TCR-induced activation of Akt whose activity we now show is required for Nur77 ubiquitination. Further analyses utilizing FAIM-deficient primary thymocytes and FAIM-overexpressing DO-11.10 T cells indicate that FAIM acts upstream of Akt during TCR signaling and influences the localization of Akt to lipid rafts, hence affecting its activation. Taken together, our study defined a TCR-induced FAIM/Akt/Nur77 signaling axis that is critical for modulating the apoptosis of developing thymocytes. |
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Authors:
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Jianxin Huo; Shengli Xu; Kong-Peng Lam |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't Date: 2010-02-23 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-12 Completed Date: 2010-05-06 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 11827-35 Citation Subset: IM |
Affiliation:
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Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / immunology, physiology* Apoptosis Regulatory Proteins / deficiency, genetics, metabolism* Caspase 9 / metabolism Enzyme Activation Membrane Microdomains / metabolism Mice Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism* Proto-Oncogene Proteins c-akt / metabolism* Receptors, Antigen, T-Cell / metabolism* Recombinant Proteins / genetics, metabolism Signal Transduction T-Lymphocyte Subsets / cytology, immunology, metabolism T-Lymphocytes / cytology*, immunology, metabolism* Transfection bcl-2 Homologous Antagonist-Killer Protein / metabolism bcl-2-Associated X Protein / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Apoptosis Regulatory Proteins; 0/Bak1 protein, mouse; 0/Bax protein, mouse; 0/Faim protein, mouse; 0/Nr4a1 protein, mouse; 0/Nuclear Receptor Subfamily 4, Group A, Member 1; 0/Receptors, Antigen, T-Cell; 0/Recombinant Proteins; 0/bcl-2 Homologous Antagonist-Killer Protein; 0/bcl-2-Associated X Protein; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.4.22.-/Casp9 protein, mouse; EC 3.4.22.-/Caspase 9 |
| Comments/Corrections | |
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