Directional protein secretion by the retinal pigment epithelium: Roles in retinal health and the development of age-related macular degeneration

Journal of Cellular and Molecular Medicine

Volumn 17, Issue 7, 2013, Pages 833-843

  Kay, Paul ^a   Yang, Yit C ^b   Paraoan, Luminita ^a  

^a UNIVERSITY OF LIVERPOOL   (United Kingdom)

^b ROYAL WOLVERHAMPTON HOSPITALS NHS TRUST   (United Kingdom)

Author keywords

Age related macular degeneration; Polarity; Protein secretion; Retina; Retinal pigment epithelium

Indexed keywords

EYE PROTEIN; SIGNAL PEPTIDE;

AGE-RELATED MACULAR DEGENERATION; ANIMAL; ARTICLE; BRUCH MEMBRANE; CHOROID; GENE EXPRESSION REGULATION; HOMEOSTASIS; HUMAN; METABOLISM; PHYSIOLOGY; PIGMENT EPITHELIUM; POLARITY; PROTEIN SECRETION; RETINA; RETINA MACULA DEGENERATION; SECRETION (PROCESS);

AGE-RELATED MACULAR DEGENERATION; POLARITY; PROTEIN SECRETION; RETINA; RETINAL PIGMENT EPITHELIUM;

ANIMALS; BRUCH MEMBRANE; CHOROID; EYE PROTEINS; GENE EXPRESSION REGULATION; HOMEOSTASIS; HUMANS; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; MACULAR DEGENERATION; RETINA; RETINAL PIGMENT EPITHELIUM;

EID: 84880815218     PISSN: 15821838     EISSN: None     Source Type: Journal    
DOI: 10.1111/jcmm.12070     Document Type: Article

References (124)

1. Hollyfield JG. Hyaluronan and the functional organization of the interphotoreceptor matrix. Invest Ophthalmol Vis Sci. 1999; 40: 2767-9.
2. Rohlich P. The interphotoreceptor matrix: electron microscopic and histochemical observations on the vertebrate retina. Exp Eye Res. 1970; 10: 80-6.
3. Ballabh P, Braun A, Nedergaard M. The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis. 2004; 16: 1-13.
4. Dornonville DL. Ion transport in the retinal pigment epithelium. A study with double barrelled ion-selective microelectrodes. Acta Ophthalmol Suppl. 1993; 209: 1-32.
5. Hamann S. Molecular mechanisms of water transport in the eye. Int Rev Cytol. 2002; 215: 395-431.
6. Miller SS, Edelman JL. Active ion transport pathways in the bovine retinal pigment epithelium. J Physiol. 1990; 424: 283-300.
7. Bok D. The retinal pigment epithelium: a versatile partner in vision. J Cell Sci Suppl. 1993; 17: 189-95.
8. Finnemann SC. Focal adhesion kinase signaling promotes phagocytosis of integrin-bound photoreceptors. EMBO J. 2003; 22: 4143-54.
9. Strauss O. The retinal pigment epithelium in visual function. Physiol Rev. 2005; 85: 845-81.
10. Ferris FL III. Senile macular degeneration: review of epidemiologic features. Am J Epidemiol. 1983; 118: 132-51.
11. Sonoda S, Spee C, Barron E, et al. A protocol for the culture and differentiation of highly polarized human retinal pigment epithelial cells. Nat Protoc. 2009; 4: 662-73.
12. Maminishkis A, Chen S, Jalickee S, et al. Confluent monolayers of cultured human fetal retinal pigment epithelium exhibit morphology and physiology of native tissue. Invest Ophthalmol Vis Sci. 2006; 47: 3612-24.
13. +, K(+)-ATPase in rat retinal pigment epithelial cells. J Histochem Cytochem. 1990; 38: 1267-75.
14. Marmorstein AD, Marmorstein LY, Rayborn M, et al. Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium. Proc Natl Acad Sci USA. 2000; 97: 12758-63.
15. Kyte J. Immunoferritin determination of the distribution of (Na+ + K+) ATPase over the plasma membranes of renal convoluted tubules. I. Distal segment. J Cell Biol. 1976; 68: 287-303.
16. Sonoda S, Sreekumar PG, Kase S, et al. Attainment of polarity promotes growth factor secretion by retinal pigment epithelial cells: relevance to age-related macular degeneration. Aging. 2010; 2: 28-42.
17. Stein MP, Wandinger-Ness A, Roitbak T. Altered trafficking and epithelial cell polarity in disease. Trends Cell Biol. 2002; 12: 374-81.
18. De S, Rabin DM, Salero E, et al. Human retinal pigment epithelium cell changes and expression of αB-crystallin: a biomarker for retinal pigment epithelium cell change in age-related macular degeneration. Arch Ophthalmol. 2007; 125: 641-5.
19. Gangalum RK, Atanasov IC, Zhou ZH, et al. αB-crystallin is found in detergent-resistant membrane microdomains and is secreted via exosomes from human retinal pigment epithelial cells. J Biol Chem. 2011; 286: 3261-9.
20. Sreekumar PG, Kannan R, Kitamura M, et al. αB crystallin is apically secreted within exosomes by polarized human retinal pigment epithelium and provides neuroprotection to adjacent cells. PLoS ONE. 2010; 5: e12578. Doi: 10.1371/journal.pone.0012578.
21. Kolomeyer AM, Sugino IK, Zarbin MA. Characterization of conditioned media collected from cultured adult versus fetal retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2011; 52: 5973-86.
22. Paskowitz DM, Nune G, Yasumura D, et al. BDNF reduces the retinal toxicity of verteporfin photodynamic therapy. Invest Ophthalmol Vis Sci. 2004; 45: 4190-6.
23. Kim YH, He S, Kase S, et al. Regulated secretion of complement factor H by RPE and its role in RPE migration. Graefes Arch Clin Exp Ophthalmol. 2009; 247: 651-9.
24. Li R, Wen R, Banzon T, et al. CNTF mediates neurotrophic factor secretion and fluid absorption in human retinal pigment epithelium. PLoS ONE. 2011; 6: e23148. Doi: 10.1371/journal.pone.0023148.
25. Paraoan L, White MR, Spiller DG, et al. Precursor cystatin C in cultured retinal pigment epithelium cells: evidence for processing through the secretory pathway. Mol Membr Biol. 2001; 18: 229-36.
26. Zurdel J, Finckh U, Menzer G, et al. CST3 genotype associated with exudative age related macular degeneration. Br J Ophthalmol. 2002; 86: 214-9.
27. Narayan S, Brun AM, Yorio T. Endothelin-1 distribution and basolateral secretion in the retinal pigment epithelium. Exp Eye Res. 2004; 79: 11-9.
28. Marmorstein LY, Munier FL, Arsenijevic Y, et al. Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration. Proc Natl Acad Sci USA. 2002; 99: 13067-72.
29. Jones RPO, Ridley C, Jowitt TA, et al. Structural effects of fibulin 5 missense mutations associated with age-related macular degeneration and cutis laxa. Invest Ophthalmol Vis Sci. 2010; 51: 2356-62.
30. Mousa SA, Lorelli W, Campochiaro PA. Role of hypoxia and extracellular matrix-integrin binding in the modulation of angiogenic growth factors secretion by retinal pigmented epithelial cells. J Cell Biochem. 1999; 74: 135-43.
31. Rosenthal R, Malek G, Salomon N, et al. The fibroblast growth factor receptors, FGFR-1 and FGFR-2, mediate two independent signalling pathways in human retinal pigment epithelial cells. Biochem Biophys Res Commun. 2005; 337: 241-7.
32. Dunn KC, Marmorstein AD, Bonilha VL, et al. Use of the ARPE-19 cell line as a model of RPE polarity: basolateral secretion of FGF5. Invest Ophthalmol Vis Sci. 1998; 39: 2744-9.
33. Kitaoka T, Morse LS, Schneeberger S, et al. Expression of FGF5 in choroidal neovascular membranes associated with ARMD. Curr Eye Res. 1997; 16: 396-9.
34. Hollborn M, Iandiev I, Seifert M, et al. Expression of HB-EGF by retinal pigment epithelial cells in vitreoretinal proliferative disease. Curr Eye Res. 2006; 31: 863-74.
35. Jin M, Yaung J, Kannan R, et al. Hepatocyte growth factor protects RPE cells from apoptosis induced by glutathione depletion. Invest Ophthalmol Vis Sci. 2005; 46: 4311-9.
36. Mochimaru H, Takahashi E, Tsukamoto N, et al. Involvement of hyaluronan and its receptor CD44 with choroidal neovascularization. Invest Ophthalmol Vis Sci. 2009; 50: 4410-5.
37. Senanayake PD, Calabro A, Nishiyama K, et al. Glycosaminoglycan synthesis and secretion by the retinal pigment epithelium: polarized delivery of hyaluronan from the apical surface. J Cell Sci. 2001; 114: 199-205.
38. Moriarty P, Boulton M, Dickson A, et al. Production of IGF-I and IGF binding proteins by retinal cells in vitro. Br J Ophthalmol. 1994; 78: 638-42.
39. Rosenthal R, Wohlleben H, Malek G, et al. Insulin-like growth factor-1 contributes to neovascularization in age-related macular degeneration. Biochem Biophys Res Commun. 2004; 323: 1203-8.
40. Burgi S, Samardzija M, Grimm C. Endogenous leukemia inhibitory factor protects photoreceptor cells against light-induced degeneration. Mol Vis. 2009; 15: 1631-7.
41. Hoffmann S, He S, Ehren M, et al. MMP-2 and MMP-9 secretion by rpe is stimulated by angiogenic molecules found in choroidal neovascular membranes. Retina. 2006; 26: 454-61.
42. Hussain AA, Lee Y, Zhang JJ, et al. Disturbed matrix metalloproteinase activity of Bruch's membrane in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011; 52: 4459-66.
43. Padgett LC, Lui GM, Werb ZENA, et al. Matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 in the retinal pigment epithelium and inter-photoreceptor matrix: vectorial secretion and regulation. Exp Eye Res. 1997; 64: 927-38.
44. Cao GF, Liu Y, Yang W, et al. Rapamycin sensitive mTOR activation mediates nerve growth factor (NGF) induced cell migration and pro-survival effects against hydrogen peroxide in retinal pigment epithelial cells. Biochem Biophys Res Commun. 2011; 414: 499-505.
45. Dawson DW, Volpert OV, Gillis P, et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science. 1999; 285: 245-8.
46. Becerra SP, Fariss RN, Wu YQ, et al. Pigment epithelium-derived factor in the monkey retinal pigment epithelium and interphotoreceptor matrix: apical secretion and distribution. Exp Eye Res. 2004; 78: 223-34.
47. Tan J, Deng ZH, Liu SZ, et al. TGF-ß2 in human retinal pigment epithelial cells: expression and secretion regulated by cholinergic signals in vitro. Curr Eye Res. 2009; 35: 37-44.
48. Yu AL, Fuchshofer R, Kook D, et al. Subtoxic oxidative stress induces senescence in retinal pigment epithelial cells via TGFß release. Invest Ophthalmol Vis Sci. 2009; 50: 926-35.
49. Wachi H, Sato F, Nakazawa J, et al. Domains 16 and 17 of tropoelastin in elastic fibre formation. Biochem J. 2007; 402: 63-70.
50. Ablonczy Z, Dahrouj M, Tang PH, et al. Human retinal pigment epithelium cells as functional models for the RPE in vivo. Invest Ophthalmol Vis Sci. 2011; 52: 8614-20.
51. Vranka JA, Johnson E, Zhu X, et al. Discrete expression and distribution pattern of TIMP-3 in the human retina and choroid. Curr Eye Res. 1997; 16: 102-10.
52. Guo L, Hussain AA, Limb GA, et al. Age-dependent variation in metalloproteinase activity of isolated human bruchs membrane and choroid. Invest Ophthalmol Vis Sci. 1999; 40: 2676-82.
53. Fariss RN, Apte SS, Olsen BR, et al. Tissue inhibitor of metalloproteinases-3 is a component of Bruch's membrane of the eye. Am J Pathol. 1997; 150: 323-8.
54. Alexander JP, Bradley JM, Gabourel JD, et al. Expression of matrix metalloproteinases and inhibitor by human retinal pigment epithelium. Invest Ophthalmol Vis Sci. 1990; 31: 2520-8.
55. Hunt RC, Fox A, al Pakalnis V, et al. Cytokines cause cultured retinal pigment epithelial cells to secrete metalloproteinases and to contract collagen gels. Invest Ophthalmol Vis Sci. 1993; 34: 3179-86.
56. Jackson C. Matrix metalloproteinases and angiogenesis. Curr Opin Nephrol Hypertens. 2002; 11: 295-9.
57. LaVail MM, Pinto LH, Yasumura D. The interphotoreceptor matrix in rats with inherited retinal dystrophy. Invest Ophthalmol Vis Sci. 1981; 21: 658-68.
58. Horwit J. Alpha-crystallin can function as a molecular chaperone. Proc Natl Acad Sci USA. 1992; 89: 10449-53.
59. Hauck SM, Schoeffmann S, Deeg C, et al. Proteomic analysis of the porcine interphotoreceptor matrix. Proteomics. 2005; 5: 3623-36.
60. Steiner C, Sahel J, Hicks D. Retinoschisin forms a multi-molecular complex with extracellular matrix and cytoplasmic proteins: interactions with beta2 laminin and alphaB-crystallin. Mol Vis. 2006; 12: 892-901.
61. Cayouette M, Smith SB, Becerra SP, et al. Pigment epithelium-derived factor delays the death of photoreceptors in mouse models of inherited retinal degenerations. Neurobiol Dis. 1999; 6: 523-32.
62. Folkman J. Angiogenesis and angiogenesis inhibition: an overview. EXS. 1997; 79: 1-8.
63. Giordano FJ, Ping P, McKirnan MD, et al. Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart. Nat Med. 1996; 2: 534-9.
64. Sensenbrenner M. The neurotrophic activity of fibroblast growth factors. Prog Neurobiol. 1993; 41: 683-704.
65. Hoppenreijs VP, Pels E, Vrensen GF, et al. Basic fibroblast growth factor stimulates corneal endothelial cell growth and endothelial wound healing of human corneas. Invest Ophthalmol Vis Sci. 1994; 35: 931-44.
66. Clements DA, Wang JK, Dionne CA, et al. Activation of fibroblast growth factor (FGF) receptors by recombinant human FGF-5. Oncogene. 1993; 8: 1311-6.
67. Stitt AW, Chakravarthy U, Gardiner TA, et al. Endothelin-like immunoreactivity and receptor binding in the choroid and retina. Curr Eye Res. 1996; 15: 111-7.
68. Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol. 2001; 41: 851-76.
69. Roberts WG, Palad GE. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci. 1995; 108: 2369-79.
70. Saint-Geniez M, Kurihara T, Sekiyama E, et al. An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris. Proc Natl Acad Sci USA. 2009; 106: 18751-6.
71. Yokomori H, Oda M, Yoshimura K, et al. Vascular endothelial growth factor increases fenestral permeability in hepatic sinusoidal endothelial cells. Liver Int. 2003; 23: 467-75.
72. Ozawa CR, Banfi A, Glazer NL, et al. Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis. J Clin Invest. 2004; 113: 516-27.
73. Barrett AJ. The cystatins: a diverse superfamily of cysteine peptidase inhibitors. Biomed Biochim Acta. 1986; 45: 1363-74.
74. Turk V, Bode W. The cystatins: protein inhibitors of cysteine proteinases. FEBS Lett. 1991; 285: 213-9.
75. Ogawa T, Boylan SA, Oltjen SL, et al. Changes in the spatial expression of genes with aging in the mouse RPE/choroid. Mol Vis. 2005; 11: 380-6.
76. Rakoczy PE, Zhang D, Robertson T, et al. Progressive age-related changes similar to age-related macular degeneration in a transgenic mouse model. Am J Pathol. 2002; 161: 1515-24.
77. Zhang D, Brankov M, Makhija MT, et al. Correlation between inactive cathepsin D expression and retinal changes in mcd2/mcd2 transgenic mice. Invest Ophthalmol Vis Sci. 2005; 46: 3031-8.
78. Walter P, Gilmore R, Blobel G. Protein translocation across the endoplasmic reticulum. Cell. 1984; 38: 5-8.
79. Mellman I, Warren G. The road taken: past and future foundations of membrane traffic. Cell. 2000; 100: 99-112.
80. Palade G. Intracellular aspects of the process of protein synthesis. Science. 1975; 189: 867-86.
81. Rothman JE, Wieland FT. Protein sorting by transport vesicles. Science. 1996; 272: 227-34.
82. Schekman R, Orci L. Coat proteins and vesicle budding. Science. 1996; 271: 1526-33.
83. Nickel W. The mystery of nonclassical protein secretion. Eur J Biochem. 2003; 270: 2109-19.
84. Fölsch H, Mattila PE, Weisz OA. Taking the scenic route: biosynthetic traffic to the plasma membrane in polarized epithelial cells. Traffic. 2009; 10: 972-81.
85. Tanos B, Rodriguez-Boulan E. The epithelial polarity program: machineries involved and their hijacking by cancer. Oncogene. 2008; 27: 6939-57.
86. Weisz OA, Rodriguez-Boulan E. Apical trafficking in epithelial cells: signals, clusters and motors. J Cell Sci. 2009; 122: 4253-66.
87. Hunziker W, Fumey C, Honing S, et al. Trafficking of immunoglobulin receptors in epithelial cells: signals and cellular factors. Cell Biol Int. 1994; 18: 321-5.
88. Keller P, Simons K. Post-Golgi biosynthetic trafficking. J Cell Sci. 1997; 110: 3001-9.
89. Mostov KE. Regulation of protein traffic in polarized epithelial cells. Histol Histopathol. 1995; 10: 423-31.
90. Rodriguez-Boulan E, Zurzolo C. Polarity signals in epithelial cells. J Cell Sci Suppl. 1993; 17: 9-12.
91. Ellis MA, Potter BA, Cresawn KO, et al. Polarized biosynthetic traffic in renal epithelial cells: sorting, sorting, everywhere. Am J Physiol Renal Physiol. 2006; 291: F707-13.
92. Rodriguez-Boulan E, Müsch A. Protein sorting in the Golgi complex: shifting paradigms. Biochim Biophys Acta. 2005; 1744: 455-64.
93. Traub LM. Common principles in clathrin-mediated sorting at the Golgi and the plasma membrane. Biochim Biophys Acta. 2005; 1744: 415-37.
94. Aroeti B, Okhrimenko H, Reich V, et al. Polarized trafficking of plasma membrane proteins: emerging roles for coats, SNAREs, GTPases and their link to the cytoskeleton. Biochim Biophys Acta. 1998; 1376: 57-90.
95. Mostov KE, Verges M, Altschuler Y. Membrane traffic in polarized epithelial cells. Curr Opin Cell Biol. 2000; 12: 483-90.
96. Yeaman CHAR, Grindstaff KK, Nelson WJ. New perspectives on mechanisms involved in generating epithelial cell polarity. Physiol Rev. 1999; 79: 73-98.
97. Gravotta D, Deora A, Perret E, et al. AP1B sorts basolateral proteins in recycling and biosynthetic routes of MDCK cells. Proc Natl Acad Sci USA. 2007; 104: 1564-9.
98. Dempse PJ, Meise KS, Coffey RJ. Basolateral sorting of transforming growth factorβ precursor in polarized epithelial cells: characterization of cytoplasmic domain determinants. Exp Cell Res. 2003; 285: 159-74.
99. Remaley AT, Hoeg JM. Polarized secretion of apoA-I and apoA-II by transfected MDCK cells. J Lipid Res. 1995; 36: 407-13.
100. Boll W, Partin JS, Katz AI, et al. Distinct pathways for basolateral targeting of membrane and secretory proteins in polarized epithelial cells. Proc Natl Acad Sci USA. 1991; 88: 8592-6.
101. Rodriguez-Boulan E, Gonzalez A. Glycans in post-Golgi apical targeting: sorting signals or structural props? Trends Cell Biol. 1999; 9: 291-4.
102. Prabakaran D, Ahima RS, Harney JW, et al. Polarized targeting of epithelial cell proteins in thyrocytes and MDCK cells. J Cell Sci. 1999; 112: 1247-56.
103. Guerriero CJ, Lai Y, Weisz OA. Differential sorting and Golgi export requirements for raft-associated and raft-independent apical proteins along the biosynthetic pathway. J Biol Chem. 2008; 283: 18040-7.
104. Jacob R, Heine M, Alfalah M, et al. Distinct cytoskeletal tracks direct individual vesicle populations to the apical membrane of epithelial cells. Curr Biol. 2003; 13: 607-12.
105. Bonilha VL, Marmorstein AD, Cohen-Gould L, et al. Apical sorting of influenza hemagglutinin by transcytosis in retinal pigment epithelium. J Cell Sci. 1997; 110: 1717-27.
106. Scheiffele P, Peranen J, Simons K. N-glycans as apical sorting signals in epithelial cells. Nature. 1995; 378: 96-8.
107. Fritz BA, Lowe AW. Polarized GP2 secretion in MDCK cells via GPI targeting and apical membrane-restricted proteolysis. Am J Physiol Gastrointest Liver Physiol. 1996; 270: G176-83.
108. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000; 100: 57-70.
109. Benussi L, Ghidoni R, Steinhoff T, et al. Alzheimer disease-associated cystatin C variant undergoes impaired secretion. Neurobiol Dis. 2003; 13: 15-21.
110. An E, Lu X, Flippin J, et al. Secreted proteome profiling in human RPE cell cultures derived from donors with age related macular degeneration and age matched healthy donors. J Proteome Res. 2006; 5: 2599-610.
111. De Strooper B, Craessaerts K, Dewachter I, et al. Basolateral secretion of amyloid precursor protein in Madin-Darby canine kidney cells is disturbed by alterations of intracellular pH and by introducing a mutation associated with familial Alzheimers disease. J Biol Chem. 1995; 270: 4058-65.
112. Zuehlke J, Ebenau A, Krueger B, et al. Vectorial secretion of CTGF as a cell-type specific response to LPA and TGF-β in human tubular epithelial cells. Cell Commun Signal. 2012; 10: 25.
113. Sonnier D, Bailey S, Schuster R, et al. TNF-alpha induces vectorial secretion of IL-8 in caco-2 cells. J Gastrointest Surg. 2010; 14: 1592-9.
114. Zhu D, Deng X, Spee C, et al. Polarized secretion of PEDF from human embryonic stem cell-derived RPE promotes retinal progenitor cell survival. Invest Ophthalmol Vis Sci. 2011; 52: 1573-85.
115. Lambert V, Wielockx B, Munaut C, et al. MMP-2 and MMP-9 synergize in promoting choroidal neovascularization. FASEB J. 2003; 17: 2290-2.
116. Crabb JW, Miyagi M, Gu X, et al. Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci USA. 2002; 99: 14682-7.
117. Sakaguchi H, Miyagi M, Shadrach KG, et al. Clusterin is present in drusen in age-related macular degeneration. Exp Eye Res. 2002; 74: 547-9.
118. Chlenski A, Liu S, Crawford SE, et al. SPARC Is a key Schwannian-derived inhibitor controlling neuroblastoma tumor angiogenesis. Cancer Res. 2002; 62: 7357-63.
119. Nozaki M, Sakurai E, Raisler BJ, et al. Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A. J Clin Invest. 2006; 116: 422-9.
120. Paraoan L, Grierson I, Maden BE. Analysis of expressed sequence tags of retinal pigment epithelium: cystatin C is an abundant transcript. Int J Biochem Cell Biol. 2000; 32: 417-26.
121. Abrahamson M, Grubb A, Olafsson I, et al. Molecular cloning and sequence analysis of cDNA coding for the precursor of the human cysteine proteinase inhibitor cystatin C. FEBS Lett. 1987; 216: 229-33.
122. Paraoan L, Grierson I, Maden BE. Fate of cystatin C lacking the leader sequence in RPE cells. Exp Eye Res. 2003; 76: 753-6.
123. Paraoan L, Ratnayaka A, Spiller DG, et al. Unexpected intracellular localization of the AMD-associated cystatin C variant. Traffic. 2004; 5: 884-95.
124. Ratnayaka A, Paraoan L, Spiller DG, et al. A dual Golgi- and mitochondria-localised Ala25Ser precursor cystatin C: an additional tool for characterising intracellular mis-localisation leading to increased AMD susceptibility. Exp Eye Res. 2007; 84: 1135-9.