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J Cell Biol. Nov 1, 1995; 131(3): 735–743.
PMCID: PMC2120616

Calcineurin functions in Ca(2+)-activated cell death in mammalian cells

Abstract

Calcineurin is a calcium-dependent protein phosphatase that functions in T cell activation. We present evidence that calcineurin functions more generally in calcium-triggered apoptosis in mammalian cells deprived of growth factors. Specifically, expression of epitope-tagged calcineurin A induces rapid cell death upon calcium signaling in the absence of growth factors. We show that this apoptosis does not require new protein synthesis and therefore calcineurin must operate through existing substrates. Co-expression of the Bcl-2 protooncogene efficiently blocks calcineurin-induced cell death. Significantly, we demonstrate that a calcium-independent calcineurin mutant induces apoptosis in the absence of calcium, and that this apoptotic response is a direct consequence of calcineurin's phosphatase activity. These data suggest that calcineurin plays an important role in mediating the upstream events in calcium-activated cell death.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Amati B, Littlewood TD, Evan GI, Land H. The c-Myc protein induces cell cycle progression and apoptosis through dimerization with Max. EMBO J. 1993 Dec 15;12(13):5083–5087. [PMC free article] [PubMed]
  • Bakhshi A, Jensen JP, Goldman P, Wright JJ, McBride OW, Epstein AL, Korsmeyer SJ. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell. 1985 Jul;41(3):899–906. [PubMed]
  • Barr PJ, Tomei LD. Apoptosis and its role in human disease. Biotechnology (N Y) 1994 May;12(5):487–493. [PubMed]
  • Caelles C, Helmberg A, Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature. 1994 Jul 21;370(6486):220–223. [PubMed]
  • Choi DW. Excitotoxic cell death. J Neurobiol. 1992 Nov;23(9):1261–1276. [PubMed]
  • Cleary ML, Sklar J. Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7439–7443. [PMC free article] [PubMed]
  • Clipstone NA, Crabtree GR. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature. 1992 Jun 25;357(6380):695–697. [PubMed]
  • Crispe IN. Fatal interactions: Fas-induced apoptosis of mature T cells. Immunity. 1994 Aug;1(5):347–349. [PubMed]
  • Debbas M, White E. Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes Dev. 1993 Apr;7(4):546–554. [PubMed]
  • Ellis RE, Yuan JY, Horvitz HR. Mechanisms and functions of cell death. Annu Rev Cell Biol. 1991;7:663–698. [PubMed]
  • Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC. Induction of apoptosis in fibroblasts by c-myc protein. Cell. 1992 Apr 3;69(1):119–128. [PubMed]
  • Fruman DA, Burakoff SJ, Bierer BE. Immunophilins in protein folding and immunosuppression. FASEB J. 1994 Apr 1;8(6):391–400. [PubMed]
  • Fruman DA, Klee CB, Bierer BE, Burakoff SJ. Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. Proc Natl Acad Sci U S A. 1992 May 1;89(9):3686–3690. [PMC free article] [PubMed]
  • Fruman DA, Mather PE, Burakoff SJ, Bierer BE. Correlation of calcineurin phosphatase activity and programmed cell death in murine T cell hybridomas. Eur J Immunol. 1992 Oct;22(10):2513–2517. [PubMed]
  • Guerini D, Klee CB. Cloning of human calcineurin A: evidence for two isozymes and identification of a polyproline structural domain. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9183–9187. [PMC free article] [PubMed]
  • Guerini D, Krinks MH, Sikela JM, Hahn WE, Klee CB. Isolation and sequence of a cDNA clone for human calcineurin B, the Ca2+-binding subunit of the Ca2+/calmodulin-stimulated protein phosphatase. DNA. 1989 Nov;8(9):675–682. [PubMed]
  • Harrington EA, Fanidi A, Evan GI. Oncogenes and cell death. Curr Opin Genet Dev. 1994 Feb;4(1):120–129. [PubMed]
  • Harrington EA, Bennett MR, Fanidi A, Evan GI. c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J. 1994 Jul 15;13(14):3286–3295. [PMC free article] [PubMed]
  • Heald R, McLoughlin M, McKeon F. Human wee1 maintains mitotic timing by protecting the nucleus from cytoplasmically activated Cdc2 kinase. Cell. 1993 Aug 13;74(3):463–474. [PubMed]
  • Hengartner MO, Horvitz HR. Activation of C. elegans cell death protein CED-9 by an amino-acid substitution in a domain conserved in Bcl-2. Nature. 1994 May 26;369(6478):318–320. [PubMed]
  • Hermeking H, Eick D. Mediation of c-Myc-induced apoptosis by p53. Science. 1994 Sep 30;265(5181):2091–2093. [PubMed]
  • Hockenbery D, Nuñez G, Milliman C, Schreiber RD, Korsmeyer SJ. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990 Nov 22;348(6299):334–336. [PubMed]
  • Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 1993 Oct 22;75(2):241–251. [PubMed]
  • Hubbard MJ, Klee CB. Functional domain structure of calcineurin A: mapping by limited proteolysis. Biochemistry. 1989 Feb 21;28(4):1868–1874. [PubMed]
  • Kerr JF, Winterford CM, Harmon BV. Apoptosis. Its significance in cancer and cancer therapy. Cancer. 1994 Apr 15;73(8):2013–2026. [PubMed]
  • Klee CB, Draetta GF, Hubbard MJ. Calcineurin. Adv Enzymol Relat Areas Mol Biol. 1988;61:149–200. [PubMed]
  • Krinks MH, Haiech J, Rhoads A, Klee CB. Reversible and irreversible activation of cyclic nucleotide phosphodiesterase: separation of the regulatory and catalytic domains by limited proteolysis. Adv Cyclic Nucleotide Protein Phosphorylation Res. 1984;16:31–47. [PubMed]
  • Lam M, Dubyak G, Chen L, Nuñez G, Miesfeld RL, Distelhorst CW. Evidence that BCL-2 represses apoptosis by regulating endoplasmic reticulum-associated Ca2+ fluxes. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6569–6573. [PMC free article] [PubMed]
  • Liu J, Farmer JD, Jr, Lane WS, Friedman J, Weissman I, Schreiber SL. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807–815. [PubMed]
  • Martin SJ, Green DR, Cotter TG. Dicing with death: dissecting the components of the apoptosis machinery. Trends Biochem Sci. 1994 Jan;19(1):26–30. [PubMed]
  • Milan D, Griffith J, Su M, Price ER, McKeon F. The latch region of calcineurin B is involved in both immunosuppressant-immunophilin complex docking and phosphatase activation. Cell. 1994 Nov 4;79(3):437–447. [PubMed]
  • O'Keefe SJ, Tamura J, Kincaid RL, Tocci MJ, O'Neill EA. FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin. Nature. 1992 Jun 25;357(6380):692–694. [PubMed]
  • Parsons JN, Wiederrecht GJ, Salowe S, Burbaum JJ, Rokosz LL, Kincaid RL, O'Keefe SJ. Regulation of calcineurin phosphatase activity and interaction with the FK-506.FK-506 binding protein complex. J Biol Chem. 1994 Jul 29;269(30):19610–19616. [PubMed]
  • Price ER, Zydowsky LD, Jin MJ, Baker CH, McKeon FD, Walsh CT. Human cyclophilin B: a second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1903–1907. [PMC free article] [PubMed]
  • Raff MC, Barres BA, Burne JF, Coles HS, Ishizaki Y, Jacobson MD. Programmed cell death and the control of cell survival: lessons from the nervous system. Science. 1993 Oct 29;262(5134):695–700. [PubMed]
  • Reed JC. Bcl-2 and the regulation of programmed cell death. J Cell Biol. 1994 Jan;124(1-2):1–6. [PMC free article] [PubMed]
  • Sentman CL, Shutter JR, Hockenbery D, Kanagawa O, Korsmeyer SJ. bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell. 1991 Nov 29;67(5):879–888. [PubMed]
  • Shi YF, Sahai BM, Green DR. Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature. 1989 Jun 22;339(6226):625–626. [PubMed]
  • Singer GG, Abbas AK. The fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity. 1994 Aug;1(5):365–371. [PubMed]
  • Smith CA, Williams GT, Kingston R, Jenkinson EJ, Owen JJ. Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature. 1989 Jan 12;337(6203):181–184. [PubMed]
  • Strasser A, Harris AW, Cory S. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell. 1991 Nov 29;67(5):889–899. [PubMed]
  • Surh CD, Sprent J. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature. 1994 Nov 3;372(6501):100–103. [PubMed]
  • Tilly JL, Hsueh AJ. Microscale autoradiographic method for the qualitative and quantitative analysis of apoptotic DNA fragmentation. J Cell Physiol. 1993 Mar;154(3):519–526. [PubMed]
  • Tsujimoto Y, Finger LR, Yunis J, Nowell PC, Croce CM. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science. 1984 Nov 30;226(4678):1097–1099. [PubMed]
  • Ucker DS, Ashwell JD, Nickas G. Activation-driven T cell death. I. Requirements for de novo transcription and translation and association with genome fragmentation. J Immunol. 1989 Dec 1;143(11):3461–3469. [PubMed]
  • Wagner AJ, Kokontis JM, Hay N. Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1. Genes Dev. 1994 Dec 1;8(23):2817–2830. [PubMed]
  • Yuan JY, Horvitz HR. The Caenorhabditis elegans genes ced-3 and ced-4 act cell autonomously to cause programmed cell death. Dev Biol. 1990 Mar;138(1):33–41. [PubMed]
  • Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell. 1993 Nov 19;75(4):641–652. [PubMed]

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