Abstract
Clusterin is a multifunctional glycoprotein complex found in virtually all body fluids and on the surface of cells lining body cavities. Demonstrated and proposed functions include the transport of lipoproteins, the inhibition of complementmediated cell lysis and the modulation of cell-cell interactions. On the basis of its elevated expression in apoptotic tissues, it was originally proposed that the protein might be casually involved in apoptosis. Here, we discuss the recent data that, in contrast to the earlier notion, suggest that clusterin expression is not enhanced, but rather is down-regulated in the cells undergoing apoptosis and that its expression in the apoptotic tissue is restricted to the vital neighboring cells. These results led to the proposal that rather than being a cell death gene, clusterin is a cell survival gene, exerting a protective function on the surving bystander cells.
Keywords
- Cold Spring Harbor
- Retinitis Pigmentosa
- Thymocyte Apoptosis
- Clusterin Expression
- Medullary Epithelial Cell
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References
Appeal D, Koch-Brandt C (1994) Sorting of a secretory protein (gp80) to the apical surface of Caco-2 cells. J Cell Sci 107: 553–559
Bettuzzi S, Hiipakka RA, Gilna P, Liao S (1989) Identification of an androgen-repressed mRNA in rat ventral prostate as coding for sulfated glycoprotein 2 by cDNA cloning and sequence analysis. Biochem J 257: 293–299
Bettuzzi S, Troiano L, Davalli P, Tropea F, Ingletti MC, Grassilli E, Monti D, Cori A, Franceschi C (1991) In vivo accumulation of sulfated glycoprotein 2 mRNA in rat thymocytes upon dexamethasone-induced cell death. Biochem Biophys Res Commun 175: 810–815
Bissonnette RP, Shi Y, Mahboubi A, Glynn JM, Green DR (1994) c-myc and apoptosis. In: Tomei LD, Cope FO (eds) Apoptosis II: the molecular basis of apoptosis in disease. Cold Spring Harbor Lab Press, New York, pp 327–356
Blaschuk O, Burdzy K, Fritz IB (1993) Purification and characterization of a cell-aggregating factor (clusterin), the major glycoprotein in ram rete testis fluid. J Biol Chem 258: 7714–7720
Brandyk M, Buttyan R, Olsson CA, Appeal G, D’Agati V, Katz A, Ng PY, Sawczuk IS (1990) TRPM-2 detection and localization during gentamicin-induced nephrotoxicity. J Urol 143: 239A
Bredesen DE (1994) Neuronal apoptosis: genetic and biochemical modulation. In: Tomei LD, Cope FO (eds) Apoptosis II: the molecular basis of apoptosis in disease. Cold Spring Harbor Lab Press, New York, pp 397–421
Brown DG, Sun XM, Cohen GM (1993) Dexamethasone-induced apoptosis involves cleavage of DNA to large fragments prior to intemucleosomal fragmentation. J Biol Chem 268: 3027–3039
Bursch W, Lauer B, Timmermann-Trosiener I, Barthel G, Schuppler J, Schulte-Hermann R (1984) Controlled cell death (apoptosis) of nonmal and putative preneoplastic cells in rat liver following withdrawal of tumor promoters. Carcinogenesis 5: 453–458
Bursch W, Oberhammer F, Schulte-Hermann R (1992a) Cell death by apoptosis and its protective role against disease. Trends Pharmacol Sci 13: 245–251
Bursch W, Fesus L, Schulte-Hermann R (1992b) Apoptosis (‘programmed’ cell death) and its relevance in liver injury and carcinogenesis. In: Dekant W, Neumann HG (eds) Tissue-specific toxicity: biochemical mechanisms. Academic Press, London, pp 95–115
Bursch W, Gleeson T, Kleine L, Tenniswood M (1995) Expression of clusterin/testosterone-repressed prostate message (TRPM-2) mRNA during growth and regression of rat liver. Arch Toxicol 69: 253–258
Buttyan R (1991) Genetic reponse of prostate cells to androgen deprivation: insights into the cellular mechanism of apoptosis. In: Tomei LD, Cope FO (eds) Apoptosis: the molecular basis of cell death. Cold Spring Harbor Lab Press, New York, pp 157–173
Buttyan R, Olsson CA, Pintar J, Chang C, Bandyk M, Ng PY, Sawczuk IS (1989) Induction of the TRPM-2 gene in cells undergoing programmed cell death. Mol Cell Biol 9: 3473–3481
Cheng YC, Mathur PP, Grima J (1988) Structural analysis of clusterin and its subunits in ram rete testis fluid. Biochemistry 27: 4079–4088
Choi-Miura NH, Takahashi Y, Nakano Y, Tobe T, Tomito M (1992) Identification of the disulfide bonds in human plasma protein SP-40, 40 (Apolipoprotein-J). J Biochem 112: 557–561
Collard MW, Griswold MD (1987) Biosynthesis and molecular cloning of sulfated glycoprotein 2 secreted by rat sertoli cells. Biochemistry 26: 3297–3303
Collins MKL, Rivas AL (1993) The control of apoptosis in mammalian cells. Trends Biochem 18: 307–309
Danik M, Chabot J-G, Mercier C, Benabid A, Chauvin C, Quirion R, Suh M (1991) Human gliomas and epileptic foci express high levels of a mRNA related to rat testicular sulfated glycoprotein 2, a purported marker of cell death. Proc Natl Acad Sci USA 88: 8577–8581
Danik M, Chabot J-G, Hassan-Gonzales D, Suh M, Quirion R (1993) Localization of sulfated glycoprotein-2/clusterin mRNA in the rat brain by in situ hybridization. J Comp Neurol 331: 209–227
Davidson NE, Lippman ME (1988) Treatment of metastatic breast cancer. In: Lippman ME, Lichter AS, Danforth DN (eds) Diagnosis and management of breast cancer. WB Saunders, London, pp 375–406
Dent AL, Matis LA, Hooshmand, F, Widacki SM, Bluestone JA, Herdick SM (1990) Self-reactive gamma delta T cells are eliminated in the thymus. Nature 343: 714–719
De Silva HV, Harmony JAK, Stuart WD, Gil CM, Robbins J (1990) Apolipoprotein J: structure and tissue distribution. Biochemistry 29: 5380–5389
Diemer V, Hoyle M, Baglioni C, Millis AJT (1992) Expression of porcine complement cytolysis inhibitor mRNA in cultured aortic smooth muscle cells. J Biol Chem 267: 5257–5264
Duguid JR, Bohmont CW, Liu N, Tourtellotte WW (1989) Changes in brain gene expression shared by scrapie and Alzheimer disease. Proc Natl Acad Sci USA 86: 7260–7264
Ellis RE, Yuan J, Horvitz HR (1991) Mechanisms and functions of cell death. Annu Rev Cell Biol 7: 663–698
English HF, Kyprianou N, Isaacs JT (1989) Relationship between DNA fragmentation and apoptosis in the programmed cell death in the rat prostate following castration. Prostate 7:41–49
Filipski J, Leblanc, J, Youdale T, Sikorska M, Walker PR (1990) Periodicity of DNA folding in higher order chromatin structures. EMBO J 9: 1319–1327
French LE, Chonn A, Ducrest D, Baumann B, Belin D, Wohlwend A, Kiss JZ, Sappino A-P, Tschopp J, Schifferli JA (1993) Molecular cloning and mRNA localization of a gene associated with epithelial differentiation processes during embryogenesis. J Cell Biol 122: 1119–1130
French LE, Sappino A-P, Tschopp J, Schifferli JA (1992) Distinct sites of production of the putative cell death marker clusterin in the human thymus. J Clin Invest 90: 1919–1925
French LE, Sappino, A-P, Tschopp J, Schifferli JA (1994a) Clusterin gene expression in the rat thymus is not modulated by dexamethasone treatment. Immunology 82: 328–331
French LE, Wohlwend A, Sappino A-P, Tschopp J, Schifferli JA (1994b) Human clusterin gene expression is confined to surviving cells during in vitro programmed cell death. J Clin Invest 93: 877–884
Fritz IB, Burdzy K (1989) Novel action of carnitine: inhibition of aggregation of dispersed cells elicited by clusterin in vitro. J Cell Physiol 140: 18–28
Fritz IB, Burdzy K, Setchell B, Blaschuk O (1983) Ram rete testis fluid contains a protein (clusterin) which influences cell-cell interactions in vitro. Biol Reprod 28: 1173–1188
Furuya Y, Berges R, Lundmo P, Isaacs JT (1994) Cell proliferation, p53 gene expression, and intracellular calcium in programmed cell death: prostate model. In: Tomei LD, Cope FO (eds) Apoptosis II: the molecular basis of apoptosis in disease. Cold Spring Harbor Lab Press, New York, pp 231–252
Garden GA, Bothwell M, Rubel EW (1991) Lack of correspondence between mRNA expression for a putative cell death molecule (SGP-2) and neuronal cell death in the central nervous system. J Neurobiol 22: 590–604
Gougeon ML, Montagnier L (1994) Apoptosis in peripheral lymphocytes during HIV infection: influence of superantigens and correlation with AIDS pathogenesis. In: Tomei LD, Cope FO (eds) Apoptosis II: the molecular basis of apoptosis in disease. Cold Spring Harbor Lab Press, New York, pp 5–20
Griswold MD, Roberts K, Bishop P (1986) Purification and characterization of sulfated glycoprotein secreted by Sertoli cells. Biochemistry 25: 7265–7270
Hartmann K, Rauch J, Urban J, Parcyk K, Diel P, Pilarsky C, Appel D, Haase W, Mann K, Weller A, Koch-Brandt C (1991) Molecular cloning of gp80, a glycoprotein complex secreted by kidney cells in vivo. J Biol Chem 266: 9924–9931
Helminen HJ, Ericson JLE (1972) Ultrastructural studies on prostatic involution in the rat. Evidence for focal irreversible damage to epithelium and heterophagic digestion in macrophages. J Ultrastruct Res 39: 443–452
Hovanessian AG (1994) Apoptosis in HIV-infection: the rule of extracellular and transmembrane glycoproteins. In: Tomei LD, Cope FO (eds) Apoptosis II: the molecular basis of apoptosis in disease. Cold Spring Harbor Lab Press, New York, pp 21–42
Humphries P, Kenna P, Farrar GJ (1992) On the molecular genetics of retinitis pigmentosa. Science 256: 804–813
Huttner WB, Gerdes H-H, Rosa P (1991) The granin (chromogranin/secretogranin) family. Trends Biochem Sci 16: 27–30
Jenne DE, Tschopp J (1989) Molecular structure and functional characterization of a human complement cytolysis inhibitor found in blood and seminal plasma: identity to sulfated glycoprotein 2, a constituent of rat testis fluid. Proc Natl Acad Sci USA 86: 7123–7127
Jenne DE, Tschopp J (1992) Clusterin: the intriguing guises of a widely expressed glycoprotein. Trends Biochem Sci 17: 154–159
Jenne DE, Lowin B, Peitsch MC, Böttcher A, Schitz G, Tschopp J (1991) Clusterin (complement lysis inhibitor) forms a high density lipoprotein complex with apolipoprotein A-1 in human plasma. J Biol Chem 266: 11030–11036
Jomary C, Murphy BF, Neal MJ, Jones SE (1993a) Abnormal distribution of retinal clusterin in retinitis pigmentosa. Mol Brain Res 20: 274–278
Jomary C, Neal MJ, Jones SE (1993b) Comparison of clusterin gene expression in normal and dystrophic human retinas. Mol Brain Res 20: 279–284
Jones SE, Wood-Gush HG, Cunningham JR, Szczesny PJ, Neal MJ (1990) Abnormalities in expression of human retinal mRNA in retinitis pigmentosa. Neurochem Int 17: 495–503
Jones SE, Meerabux JMA, Yeats DA, Neal MJ (1992) Analysis of differentially expressed genes in retinitis pigmentosa retinas: altered expression of clusterin mRNA. FEBS Lett 300: 279–282
Jordan-Starck TC, Witte DP, Aronow BJ, Harmony JAK (1992) Apolipoprotein J: a membrane policeman. Curr Opin Lipidol 3: 75–85
Kadomatsu K, Anzano MA, Slayter V, Winokur TS, Smith JM, Sporn MB (1993) Expression of sulfated glycoprotein 2 is associated with carcinogenesis induced by N-nitroso-N-methylurea in rat prostate and seminal vesicle. Cancer Res 53: 1480–1483
Kerr JFR, Harmon BV (1991) Definition and incidence of apoptosis: an historical perspective. In: Tomei LD, Cope FO (eds) Apoptosis: the molecular basis of cell death. Cold Spring Harbor Lab Press, New York, pp 5–30
Kirszbaum L, Sharpe JA, Murphy B, d’Apice JF, Classon B, Hudson P, Walker ID (1989) Molecular cloning and characterization of the noval, human complement-associated protein, SP 40, 40: a link between the complement and reproductive systems. EMBO J 8: 711–718
Kirszbaum L, Bozas WE, Walker ID (1992) SP-40, 40, a protein involved in the control of the complement pathway, possesses a unique array of disulphide bridges. FEBS Lett 297: 70–76
Kounnas MZ, Loukinova EB, Stefansson S, Harmony JAK, Brewer BH, Strickland DK, Argraves WS (1995) Identification of glycoprotein 330 as an endocytic receptor for Apolipoprotein J/ Clusterin. J Biol Chem 270: 13070–13075
Kure S, Tominaga T, Yoshimoto T, Tada K, Narisawa K (1991) Glutamate triggers internucleosomal DNA cleavage in neuronal cells. Biochem Biophys Res Commun 179: 39–46
Kyprianou N, English HF, Isaacs JT (1988) Activation of a Ca++-Mg++-dependent endonuclease as an early event in castration-induced prostate cell death. Prostate 13: 103–109
Kyprianou N, English HF, Isaacs JT (1990) Programmed cell death during the regression of PC-82 human prostate cancer following androgen ablation. Cancer Res 50: 3748–3753
Kyprianou N, English HF, Davidson NE, Isaacs JT (1991) Programmed cell death during regression of the MCF-7 human breast cancer following estrogen ablation. Cancer Res 51: 162–166
Laping NJ, Morgan TE, Nichols NR, Rozovsky I, Young-Chan Cs, Zarow C, Finch CE (1994) Transforming growth factor-β1 induces neuronal and astrocyte genes: tubulin α1, glial fibrillary acidic protein and clusterin. Neuroscience 58: 563–572
Laslop A, Steiner H-J, Egger C, Wolkersdorfer M, Kapelari S, Hogue-Angeletti R, Erickson JD, Fischer-Colbrie R, Winkler H (1993) Glycoprotein III (clusterin, sulfated glycoprotein 2) in endocrine, nervous, and other tissues: immunochemical characterization, subcellular localization, and regulation of bisynthesis. J Neurochem 61: 1498–1505
Lee S, Christakos S, Small MB (1993) Apoptosis and signal transduction: clues to a molecular mechanism. Curr Op in Cell Biol 5: 286–291
MacDonald HR, Lees RK (1990) Programmed death of autoreactive thymocytes. Nature 343: 642–644
Martin SJ (1993) Apoptosis: suicide, execution or murder. Trends Cell Biol 3: 141–144
May PC, Finch CE (1992) Sulfated glycoprotein 2: new relationships of this multifunctional protein to neurodegeneration. Trends Neurosci 15: 391–396
May PC, Lampert-Etchells M, Johnson SA, Poirier J, Masters JN, Finch CE (1990) Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer’s disease and in response to experimental lesions in rat. Neuron 5: 831–839
May PC, Robinson P, Fuson K, Smalstig B, Stephenson D, Clemens JA (1992) Sulfated glycoprotein- 2 expression increases in rodent brain after transient global ischemia. Mol Brain Res 15: 33–39
Michel D, Gillet G, Volovitch M, Pessac B, Calothy G, Brun G (1989) Expression of a noval gene encoding a 51.5 kD precursor protein is induced by different retroviral oncogenes in quail neuroretinal cells. Oncogene Res 4: 127–136
Montpetit ML, Lawless KR, Tenniswood M (1986) Androgen-repressed messages in the rat ventral prostate. Prostate 8: 25–36
Murphy BF, Kirszbaum L, Walker ID, d’Apice AJF (1988) SP-40, 40 a newly identified normal human serum protein found in the SC5b-9 complex of complement and in the immune deposits in glomerulonephritis. J Clin Invest 81: 1858–1864
Nagata S (1994) Apoptosis-mediating Fas antigen and its natural mutation. In: Tomei LD, Cope FO (eds) Apoptosis II: the molecular basis of apoptosis in disease. Cold Spring Harbor Lab Press, New York, pp 313–326
Oberhammer F, Wilson JW, Dive C, Morris ID, Hickman JA, Wakeling AE, Walker PR, Sikorska M (1993) Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. EMBO J 12: 3679–3684
O’Bryan MK, Cheema SS, Barlett PF, Murphy BF, Pearse MJ (1993) Clusterin levels increase during neuronal development. J Neurobiol 25: 421–432
Osborne BA, Schwartz LM (1994) Essential genes that regulate apoptosis. Trends Cell Biol 4: 394–399
Palmar DJ, Christie DL (1990) The primary structure of glycoprotein III from bovine adrenal meduallary chromaffin granules. J Biol Chem 265: 6617–6623
Parczyk K, Pilarsky C, Rachel U, Koch-Brandt C (1994) Gp80 (clusterin; TRPM-2) mRNA level is enhanced in human renal clear cell carcinomas. J Cancer Res Clin Oncol 120: 186–188
Pasinetti GM, Johnson SA, Oda T, Rozovsky I, Finch CE (1994) Clusterin (SGP-2): a multifunctional glycoprotein with regional expression in astrocytes and neurons of the adult rat brain. J Comp Neurol 339: 387–400
Peitsch MC, Mannherz HG, Tschopp J (1994) The apoptosis endonucleases: cleaning up after cell death? Trends Cell Biol 4: 37–41
Pignataro OP, Feng Z-M, Chen C (1992) Cyclic adenosine 3′, 5′ -monophosphate negatively regulates clusterin gene expression in Leydig tumor cell lines. Endocrinology 130: 2745–2750
Pilarsky C, Haase W, Koch-Brandt C (1993) Stable expression of gp80 (TRPM-2, clusterin), a secretory protein implicated in programmed cell death, in transfected BHK-21 cells. Biochim Biophys Acta 1179: 306–310
Purello M, Betuzzi S, DiPietro C, Mirabile E, Di Blasi M, Rimini R, Grzeschik KH, Ingletti C, Corti A, Sichel G (1991) The gene for SP-40,40, human homolog of rat sulfated glycoprotein 2 rat clusterin, and rat testosterone-repressed prostatic message 2, maps to chromosome 8. Genomics 10: 151–156
Raff MC (1992) Social controls on cell survival and cell death. Nature 356: 397–400
Rennie PS, Bruchovsky N, Buttyan R, Benson M, Cheng H (1988) Gene expression during the early phases of regression of the androgen-dependent Shionogi mouse mammary carcinoma. Cancer Res 48: 6309–6312
Sawczuk IS, Hoke Olsson CA, Connor J, Buttyan R (1989) Gene expression in response to acute unilateral ureteral obstruction. Kidney Int 35: 1315–1321
Sensibar JA, Griswold MD, Sylvester SR, Buttyan R, Bardin CW, Cheng CY, Dudek S, Lee C (1991) Prostatic ductal system in rats: regional variation in localization of an androgen-repressed gene product, sulfated glycoprotein-2. Endocrinology 128: 2091–2102
Sloviter RS, Sollas AL, Dean E, Neubart S (1993) Adrenalectomy-induced granule cell degeneration in the rat hippocampal dentate gyrus: characterization of an in vivo model of controlled neuronal death. J Comp Neurol 330: 324–336
Smith CA, Williams GT, Kingston R, Jenkinson EJ, Owen JJT (1989) Antibodies to CD3/T cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature 337: 181–184
Smith CA, Grimes EA, McCarthy NJ, Williams GT (1994) Multiple gene regulation of apoptosis: Significance in immunology and oncology. In: Tomei LD, Cope FO (eds) Apoptosis II: the molecular basis of apoptosis in disease. Cold Spring Harbor Press, New York, pp 43–88
Tenniswood M, Taillefer D, Lakins J, Guenette R, Mooibroek M, Daehlin L, Welsh J (1994) Control of gene expression during apoptosis in hormone-dependent tissues. In: Tomei LD, Cope FO (eds) Apoptosis II: the molecular basis of apoptosis in disease. Cold Spring Harbor Lab Press, New York, pp 283–311
Tschopp J, Jenne DE, Hertig S, Preissner KT, Morgenstern H, Sapino A-P, French L (1993) Human megakaryocytes express clusterin and package it without apolipoprotein A-1 into α-granules. Blood 82: 118–125
Urban J, Parczyk K, Leutz A, Kayne M, Kondor-Koch C (1987) Constitutive apical secretion of an 80-kD sulfated glycoprotein complex in the polarized epithelial Madin-Darby canine kidney cell line. J Cell Biol 105: 2735–2743
Van der Wal EA, Gomez-Pinilla F, Cotman CW (1993) Transforming growth factor-β1 is in plaques in Alzheimer and Down pathologies. Neuro Rep 4: 69–72
Wadewitz AG, Lockshin RA (1988) Programmed cell death: dying cells synthesize a co-ordinated, unique set of proteins in two different episodes of cell death. FEBS Lett 241: 19–23
White E, Gooding LR (1994) Regulation of apoptosis by human adenoviruses. In: Tomei LD, Cope FO (eds) Apoptosis II: the molecular basis of apoptosis in disease. Cold Spring Harbor Lab Press, New York, pp 111–142
White K, Grether ME, Abrams JM, Young L, Farrell K, Steller H (1994) Genetic control of programmed cell death in Drosophila. Science 264: 677–683
Wiessner C, Back T, Bonnekoh P, Kohno K, Gehrmann J, Hossmann KA (1993) Sulfated glycoprotein-2 mRNA in the rat brain following transient forebrain ischemia. Mol Brain Res 20: 345–352
Williams GT (1991) Programmed cell death: apoptosis and oncogenesis. Cell 65: 1097–1098
Williams GT, Smith CA (1993) Molecular regulation of apoptosis: genetic controls on cell death. Cell 74: 777–779
Williams GT, Smith CA, McCarthy NJ, Grimes EA (1992) Apoptosis: final control point in cell biology. Trends Cell Biol 2: 263–267
Witte DP, Aronow BJ, Staudermann ML, Stuart WD, Clay MA, Gruppo R, Jenkins SH, Harmony JAK (1993) Platelet activation releases megakaryocyte-synthesized apolipoprotein J, a highly abundant protein in atheromatous lesions. Am J Pathol 143: 763–773
Wong P, Pineault JM, Lakins J, Taillefer D, Leger JG, Wang C, Tenniswood MP (1993) Genomic organisation and expression of the rat TRPM-2 (clusterin) gene, a gene implicated in apoptosis. J Biol Chem 268: 5021–5031
Wyllie AH (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284: 555–556
Wyllie AH (1985) The biology of cell death in tumors. Anticancer Res 5: 131–136
Yasuhara O, Aimi Y, McGeer E, McGeer P (1994) Expression of the complement membrane attack complex and its inhibitors in pig-disease brain. Brain Res 652: 346–349
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Koch-Brandt, C., Morgans, C. (1996). Clusterin: A Role in Cell Survival in the Face of Apoptosis?. In: Kuchino, Y., Müller, W.E.G. (eds) Apoptosis. Progress in Molecular and Subcellular Biology, vol 16. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-79850-4_8
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