PMID: 8939689Sep 1, 1996Paper

Controlling programmed cell death with a cyclophilin-cyclosporin-based chemical inducer of dimerization

Chemistry & Biology
P J BelshawS L Schreiber

Abstract

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. (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. C...Continue Reading

References

Jan 1, 1991·Annual Review of Immunology·P L Cohen, R A Eisenberg
Sep 1, 1987·European Journal of Immunology·V F QuesniauxM H Van Regenmortel
Nov 2, 1984·Science·R E HandschumacherD W Speicher
Mar 10, 1995·Science·S Nagata, P Golstein
Oct 10, 1995·Proceedings of the National Academy of Sciences of the United States of America·D M SpencerG R Crabtree
Oct 10, 1995·Proceedings of the National Academy of Sciences of the United States of America·L J HolsingerG R Crabtree
Nov 12, 1993·Science·D M SpencerG R Crabtree
May 19, 1995·Cell·J L Cleveland, J N Ihle
Aug 30, 1994·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·M O Hengartner, H R Horvitz
May 14, 1996·Proceedings of the National Academy of Sciences of the United States of America·P J BelshawS L Schreiber
Jun 14, 1996·Cell·A Fraser, G Evan
Jul 1, 1996·Current Biology : CB·D M SpencerS L Schreiber
Nov 1, 1994·Chemistry & Biology·D J AustinS L Schreiber
Nov 1, 1994·Chemistry & Biology·M N PruschyS L Schreiber

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Citations

Nov 5, 2003·Journal of Molecular Biology·Rachel S Signarvic, William F DeGrado
May 5, 2001·Pharmacology & Therapeutics·K SharmaY F Shi
Nov 10, 2000·Advanced Drug Delivery Reviews·K J HarringtonR G Vile
Jun 12, 2008·Analytical Chemistry·Eric T MackGeorge M Whitesides
Oct 9, 1999·Human Gene Therapy·L FanD M Spencer
Mar 17, 2011·Science Signaling·Fu-Sen LiangGerald R Crabtree
May 23, 1998·Annual Review of Immunology·J D KlemmG R Crabtree
Jun 22, 2000·Proceedings of the National Academy of Sciences of the United States of America·S ParkG L Verdine
Dec 18, 2002·Proceedings of the National Academy of Sciences of the United States of America·S W Michnick, F-X Campbell Valois
Jul 22, 1997·Proceedings of the National Academy of Sciences of the United States of America·S D LiberlesS L Schreiber
Dec 17, 2014·Clinical & Translational Immunology·Siok-Keen Tey
May 9, 1998·Proceedings of the National Academy of Sciences of the United States of America·R A MacCorkleD M Spencer
Oct 6, 1997·Proceedings of the National Academy of Sciences of the United States of America·J F AmaraM Gilman
Aug 15, 2000·Annual Review of Biophysics and Biomolecular Structure·A BishopK M Shokat
Dec 17, 2014·Frontiers in Pharmacology·Benjamin S JonesAntonio Di Stasi
Sep 10, 2003·Chembiochem : a European Journal of Chemical Biology·Nils Johnsson, Kai Johnsson
Jun 13, 2012·Angewandte Chemie·Anna Rutkowska, Carsten Schultz
Aug 8, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Katerina Cermakova, H Courtney Hodges
May 16, 2012·FEBS Letters·Mateusz Putyrski, Carsten Schultz
Apr 24, 2007·Angewandte Chemie·Li ZhangLuc Brunsveld
Apr 4, 2009·Organic & Biomolecular Chemistry·Motofumi OsakiAkira Harada
Sep 3, 2010·Chembiochem : a European Journal of Chemical Biology·Kimberly J Peterson-KaufmanAseem Z Ansari
Jul 5, 2007·Organic & Biomolecular Chemistry·Casey J Krusemark, Peter J Belshaw
Feb 9, 2017·Oncotarget·Ping LiQiang Li
Dec 14, 2016·Annual Review of Pathology·Jonathan H EsenstenWendell A Lim
Dec 23, 2014·Chembiochem : a European Journal of Chemical Biology·Catherine W WrightFu-Sen Liang
Dec 21, 2018·Frontiers in Pharmacology·Jürgen M KolosFelix Hausch
Mar 29, 2018·Science·Benjamin Z StantonGerald R Crabtree
May 27, 2004·Organic & Biomolecular Chemistry·Mónica GarcíaAnna Diez
Aug 31, 2016·The Biochemical Journal·Amy E Campbell, Daimark Bennett
Feb 14, 2002·Chemistry & Biology·Paul A ClemonsStuart L Schreiber
May 29, 2021·RSC Medicinal Chemistry·Lewis L BrayshawChristopher Herring
Aug 15, 2017·ACS Chemical Biology·Dominic Kamps, Leif Dehmelt
Dec 2, 2000·The Journal of Organic Chemistry·J Pérez SesteloL A Sarandeses
Jun 15, 2006·Chemical Reviews·Daniel P Walsh, Young-Tae Chang
Jun 19, 2001·Genes & Development·A A Mills

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis