The CLU gene contains nine exons and expresses three isoforms alternatively-spliced at the first exon.[3] The encoded protein isoforms all localize to different subcellular compartments: one isoform localizes to the nucleus; a second isoform localizes to the cytoplasm; and the third is secreted from the cell.[3][5] They also perform opposing functions: the nuclear CLU binds Ku70 to release BAX and induce apoptosis, whereas the cytosolic and secretory isoforms inhibit apoptosis.[3][4] The nuclear isoform encodes a 49 kDa protein, while the secretory isoform, which is the main gene transcript, encodes a 75–80 kDa protein after maturation (glycosylation, secretion, and dimerization).[3][4] The mature protein is a 449-residue, heterodimeric, disulfide-linked glycoprotein composed of two subunits of 40 kDa α- and β-chains.[3][4][5]
Clusterin was first identified in ram rete testis fluid where it showed signs of clustering with rat sertoli cells and erythrocytes, hence its name.[6]
CLU is a member of the small heat shock protein family and, thus, a molecular chaperone. Unlike most other chaperone proteins, which aid intracellular proteins, CLU is a Golgi chaperone that facilitates the folding of secreted proteins in an ATP-independent way.[5] The gene is highly conserved in species, and the protein is widely distributed in many tissues and organs, where it participates in a number of biological processes, including lipid transport, membrane recycling, cell adhesion, programmed cell death, and complement-mediated cell lysis.[3][4][5] Overexpression of the secretory CLU isoform protects the cell from apoptosis induced by cellular stress, such as chemotherapy, radiotherapy, or androgen/estrogen depletion. CLU promotes cell survival by a number of means, including inhibition of BAX on the mitochondrial membrane, activation of the phosphatidylinositol 3-kinase/protein kinase B pathway, modulation of extracellularular signal-regulated kinase (ERK) 1/2 signaling and matrix metallopeptidase-9 expression, promotion of angiogenesis, and mediation of the nuclear factor kappa B (NF-κB) pathway. Meanwhile, its downregulation allows for p53 activation, which then skews the proapoptotic:antiapoptotic ratio of present Bcl-2 family members, resulting in mitochondrial dysfunction and cell death. p53 may also transcriptionally repress secretory CLU to further promote the proapoptotic cascade.[3]
Two independent genome-wide association studies found a statistical association between a SNP within the clusterin gene and the risk of having Alzheimer's disease. Further studies have suggested that people who already have Alzheimer's disease have more clusterin in their blood, and that clusterin levels in blood correlate with faster cognitive decline in individuals with Alzheimer's disease, but have not found that clusterin levels predicted the onset of Alzheimer's disease.[7][8][9][10] In addition to Alzheimer’s disease, CLU is involved in other neurodegenerative diseases such as Huntington disease.[4]
As evident by its key roles in cancer development, CLU can serve as a therapeutic target for fighting tumor growth and chemoresistance. Studies revealed that inhibition of CLU resulted in increased effectiveness of chemotherapeutic agents to kill tumor cells.[3] In particular, custirsen, an antisense oligonucleotide that blocks the CLU mRNA transcript, enhanced heat-shock protein 90 (HSP90) inhibitor activity by suppressing the heat-shock response in castrate-resistant prostate cancer, and is currently in phase III trials.[3][5]
↑ 5.05.15.25.35.45.55.65.7Lin CC, Tsai P, Sun HY, Hsu MC, Lee JC, Wu IC, Tsao CW, Chang TT, Young KC (Nov 2014). "Apolipoprotein J, a glucose-upregulated molecular chaperone, stabilizes core and NS5A to promote infectious hepatitis C virus virion production". Journal of Hepatology. 61 (5): 984–93. doi:10.1016/j.jhep.2014.06.026. PMID24996046.
↑Fritz IB, Burdzy K, Sétchell B, Blaschuk O (Jun 1983). "Ram rete testis fluid contains a protein (clusterin) which influences cell-cell interactions in vitro". Biology of Reproduction. 28 (5): 1173–88. doi:10.1095/biolreprod28.5.1173. PMID6871313.
↑Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, Heun R, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J (Oct 2009). "Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease". Nature Genetics. 41 (10): 1088–93. doi:10.1038/ng.440. PMC2845877. PMID19734902. Lay summary – TIME Magazine (2009-09-06).
↑Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanché H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alpérovitch A, Lathrop M, Amouyel P (Oct 2009). "Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease". Nature Genetics. 41 (10): 1094–9. doi:10.1038/ng.439. PMID19734903.
↑Schrijvers EM, Koudstaal PJ, Hofman A, Breteler MM (Apr 2011). "Plasma clusterin and the risk of Alzheimer disease". JAMA. 305 (13): 1322–6. doi:10.1001/jama.2011.381. PMID21467285.
Krumbiegel M, Pasutto F, Mardin CY, Weisschuh N, Paoli D, Gramer E, Zenkel M, Weber BH, Kruse FE, Schlötzer-Schrehardt U, Reis A (Jun 2009). "Exploring functional candidate genes for genetic association in german patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma". Investigative Ophthalmology & Visual Science. 50 (6): 2796–801. doi:10.1167/iovs.08-2339. PMID19182256.
Trougakos IP, Gonos ES (Nov 2002). "Clusterin/apolipoprotein J in human aging and cancer". The International Journal of Biochemistry & Cell Biology. 34 (11): 1430–48. doi:10.1016/S1357-2725(02)00041-9. PMID12200037.
Jenne DE, Tschopp J (Apr 1992). "Clusterin: the intriguing guises of a widely expressed glycoprotein". Trends in Biochemical Sciences. 17 (4): 154–9. doi:10.1016/0968-0004(92)90325-4. PMID1585460.
Ståhl AL, Kristoffersson A, Olin AI, Olsson ML, Roodhooft AM, Proesmans W, Karpman D (Jul 2009). "A novel mutation in the complement regulator clusterin in recurrent hemolytic uremic syndrome". Molecular Immunology. 46 (11–12): 2236–43. doi:10.1016/j.molimm.2009.04.012. PMID19446882.
Balantinou E, Trougakos IP, Chondrogianni N, Margaritis LH, Gonos ES (May 2009). "Transcriptional and posttranslational regulation of clusterin by the two main cellular proteolytic pathways". Free Radical Biology & Medicine. 46 (9): 1267–74. doi:10.1016/j.freeradbiomed.2009.01.025. PMID19353783.
Wei L, Xue T, Wang J, Chen B, Lei Y, Huang Y, Wang H, Xin X (Aug 2009). "Roles of clusterin in progression, chemoresistance and metastasis of human ovarian cancer". International Journal of Cancer. 125 (4): 791–806. doi:10.1002/ijc.24316. PMID19391138.
Chou TY, Chen WC, Lee AC, Hung SM, Shih NY, Chen MY (May 2009). "Clusterin silencing in human lung adenocarcinoma cells induces a mesenchymal-to-epithelial transition through modulating the ERK/Slug pathway". Cellular Signalling. 21 (5): 704–11. doi:10.1016/j.cellsig.2009.01.008. PMID19166932.
Olsen SH, Ma L, Schnitzer B, Fullen DR (Mar 2009). "Clusterin expression in cutaneous CD30-positive lymphoproliferative disorders and their histologic simulants". Journal of Cutaneous Pathology. 36 (3): 302–7. doi:10.1111/j.1600-0560.2008.01036.x. PMID19220628.
Aigelsreiter A, Janig E, Sostaric J, Pichler M, Unterthor D, Halasz J, Lackner C, Zatloukal K, Denk H (Apr 2009). "Clusterin expression in cholestasis, hepatocellular carcinoma and liver fibrosis". Histopathology. 54 (5): 561–70. doi:10.1111/j.1365-2559.2009.03258.x. PMID19413638.
Trougakos IP, Lourda M, Antonelou MH, Kletsas D, Gorgoulis VG, Papassideri IS, Zou Y, Margaritis LH, Boothman DA, Gonos ES (Jan 2009). "Intracellular clusterin inhibits mitochondrial apoptosis by suppressing p53-activating stress signals and stabilizing the cytosolic Ku70-Bax protein complex". Clinical Cancer Research. 15 (1): 48–59. doi:10.1158/1078-0432.CCR-08-1805. PMID19118032.
Boland JM, Folpe AL, Hornick JL, Grogg KL (Aug 2009). "Clusterin is expressed in normal synoviocytes and in tenosynovial giant cell tumors of localized and diffuse types: diagnostic and histogenetic implications". The American Journal of Surgical Pathology. 33 (8): 1225–9. doi:10.1097/PAS.0b013e3181a6d86f. PMID19542874.
Chandra P, Plaza JA, Zuo Z, Diwan AH, Koeppen H, Duvic M, Medeiros LJ, Prieto VG (Apr 2009). "Clusterin expression correlates with stage and presence of large cells in mycosis fungoides". American Journal of Clinical Pathology. 131 (4): 511–5. doi:10.1309/AJCPH43ZDVLSOSNB. PMID19289586.
Rizzi F, Caccamo AE, Belloni L, Bettuzzi S (May 2009). "Clusterin is a short half-life, poly-ubiquitinated protein, which controls the fate of prostate cancer cells". Journal of Cellular Physiology. 219 (2): 314–23. doi:10.1002/jcp.21671. PMID19137541.
Liao FT, Lee YJ, Ko JL, Tsai CC, Tseng CJ, Sheu GT (May 2009). "Hepatitis delta virus epigenetically enhances clusterin expression via histone acetylation in human hepatocellular carcinoma cells". The Journal of General Virology. 90 (Pt 5): 1124–34. doi:10.1099/vir.0.007211-0. PMID19264665.
Shannan B, Seifert M, Boothman DA, Tilgen W, Reichrath J (Sep 2006). "Clusterin and DNA repair: a new function in cancer for a key player in apoptosis and cell cycle control". Journal of Molecular Histology. 37 (5–7): 183–8. doi:10.1007/s10735-006-9052-7. PMID17048076.
Shannan B, Seifert M, Leskov K, Willis J, Boothman D, Tilgen W, Reichrath J (Jan 2006). "Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer". Cell Death and Differentiation. 13 (1): 12–9. doi:10.1038/sj.cdd.4401779. PMID16179938.
Otowa T, Yoshida E, Sugaya N, Yasuda S, Nishimura Y, Inoue K, Tochigi M, Umekage T, Miyagawa T, Nishida N, Tokunaga K, Tanii H, Sasaki T, Kaiya H, Okazaki Y (Feb 2009). "Genome-wide association study of panic disorder in the Japanese population". Journal of Human Genetics. 54 (2): 122–6. doi:10.1038/jhg.2008.17. PMID19165232.
Tunçdemir M, Ozturk M (Dec 2008). "The effects of ACE inhibitor and angiotensin receptor blocker on clusterin and apoptosis in the kidney tissue of streptozotocin-diabetic rats". Journal Mol ecular Histology. 39 (6): 605–16. doi:10.1007/s10735-008-9201-2. PMID18949565.
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