التفاصيل البيبلوغرافية
| العنوان: |
Controlling programmed cell death with a cyclophilincyclosporin-based chemical inducer of dimerization |
| المؤلفون: |
Stuart L. Schreiber, Peter J. Belshawl, David M. Spencer, Gerald R. Crabtree |
| المصدر: |
Chemistry & Biology. (9):731-738 |
| بيانات النشر: |
Published by Elsevier Ltd. |
| مصطلحات موضوعية: |
Clinical Biochemistry, Gene Expression, 01 natural sciences, Jurkat cells, Biochemistry, Fas ligand, Genes, Reporter, Cyclosporin a, Drug Discovery, chemical inducer of dimerization, Fluorometry, Cloning, Molecular, Cells, Cultured, Amino Acid Isomerases, 0303 health sciences, Membrane Glycoproteins, Molecular Structure, Histocytochemistry, apoptosis, Nuclear Proteins, General Medicine, Peptidylprolyl Isomerase, Fas receptor, Cell biology, DNA-Binding Proteins, cyclophilin, Cyclosporine, Molecular Medicine, Dimerization, Protein Binding, Signal Transduction, Cell signaling, Fas Ligand Protein, Recombinant Fusion Proteins, Blotting, Western, Biology, Transfection, Models, Biological, 03 medical and health sciences, Humans, Molecular Biology, 030304 developmental biology, Pharmacology, NFATC Transcription Factors, 010405 organic chemistry, Fusion protein, 0104 chemical sciences, cyclosporin, Apoptosis, Fas signaling pathway, Carrier Proteins, Transcription Factors |
| الوصف: |
Background : Cell death can occur either from physical damage (necrosis) or cellular suicide (apoptosis). Apoptosis is essential for the development of multicellular organisms and disregulated apoptosis underlies many human diseases. The Fas receptor (Fas) is a membrane signaling protein that mediates a death signal following its aggregation by the Fas ligand. We have described methods to induce the association of proteins using cell-permeable molecules called chemical inducers of dimerization (CIDs). Here we describe the synthesis of a novel CID, (CsA) 2 , that has two identical protein-binding surfaces derived from the immunosuppressant cyclosporin A (CsA). We use this CID to deliver a death signal to cells expressing a fusion protein containing cyclophilin (CyP, the protein receptor for cyclosporin) and the cytoplasmic signaling domain of Fas. Results : (CsA) 2 was synthesized in six synthetic steps and 30 % overall yield from cyclosporin. It binds to two CyP proteins simultaneously, but does not inhibit T -cell signaling, presumably because the (CsA) 2 -CyP complex does not bind to calcineurin. Jurkat cells stably transfected with constructs encoding myristoylated CyP-Fas fusion proteins undergo apoptosis in response to nanomolar quantities of (CsA) 2 . Constructs containing a mutation in the myristoylation signal are defective for signaling. Conclusions : The Fas signaling pathway can be activated with a cell-permeable CID derived from CsA in cells expressing an appropriately engineered Fas construct, which must be localized at the membrane. This new class of homodimerizing CIDs will be useful for in-depth analysis of protein association events in complex systems, including transgenic animals. Now that several CIDs with distinct dimerization characteristics are available, it should be possible to induce the activation of multiple pathways with complete specificity. |
| اللغة: |
English |
| تدمد: |
1074-5521 |
| DOI: |
10.1016/S1074-5521(96)90249-5 |
| URL الوصول: |
https://explore.openaire.eu/search/publication?articleId=doi_dedup___::95298fc814c4b0e719987600836b93a9 |
| Rights: |
OPEN |
| رقم الانضمام: |
edsair.doi.dedup.....95298fc814c4b0e719987600836b93a9 |
| قاعدة البيانات: |
OpenAIRE |