Atlas of Genetics and Cytogenetics in Oncology and Haematology

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CLU (clusterin)

Written2009-10Hanna Rauhala, Tapio Visakorpi
Institute of Medical Technology, University of Tampere, Tampere University Hospital, Tampere, Finland

(Note : for Links provided by Atlas : click)


Other aliasAAG4
LocusID (NCBI) 1191
Atlas_Id 40107
Location 8p21.1  [Link to chromosome band 8p21]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ATP5B (12q13.3) / CLU (8p21.1)C16orf52 (16p12.2) / CLU (8p21.1)CLU (8p21.1) / ADD3 (10q25.1)
CLU (8p21.1) / AGT (1q42.2)CLU (8p21.1) / CDK9 (9q34.11)CLU (8p21.1) / CLU (8p21.1)
CLU (8p21.1) / FER1L4 (20q11.22)CLU (8p21.1) / MACF1 (1p34.3)CLU (8p21.1) / MAP2K2 (19p13.3)
CLU (8p21.1) / NEGR1 (1p31.1)CLU (8p21.1) / RAB3C (5q11.2)CLU (8p21.1) / ZBTB18 (1q44)
CLU (8p21.1) / ZFAND2B (2q35)COL3A1 (2q32.2) / CLU (8p21.1)DIS3L (15q22.31) / CLU (8p21.1)
LONRF2 (2q11.2) / CLU (8p21.1)PEG10 (7q21.3) / CLU (8p21.1)UBE2V1 (20q13.13) / CLU (8p21.1)


  A) Clusterin gene genomic location at chromosome 8p21-p12 (minus strand) and annotated transcripts. B) Exons are numbered and presented by boxes. Shaded areas represent untranslated regions (UTR). Endoplastic reticulum (ER)-targeting signal in exon 2 and nuclear localization signal (NLS) in exon 3 are marked. Three in-frame translation start sites in exons 1, 2 and 3 are marked (ATG).
Description Clusterin gene is 17876 bp long and contains 10 exons in total. First two exons are alternative (designated 1 and 1') used by two different transcript isoforms. Other exons (2-9) are shared with both isoforms. CLU gene resides in minus strand and is transcribed in reverse orientation (from centromere to p-telomere).
Transcription Clusterin gene is transcribed into 2 mRNA isoforms (NM-001831, 2859 bp; and NM-203339, 2979 bp). They result from the use of alternative first exons (1 and 1') and shared exons 2 to 9.


  Clusterin transcripts contain 3 different translation start sites (ATG), all in-frame. The best characterized protein isoform is produced from transcript isoform 2, where translation starts at the second ATG present in exon 2, right before ER-targeting signal. This protein (NP-976084) consists of 449 amino acids. The mechanism by which the protein products are translated from isoform 1 is not as well understood. There is evidence suggesting that two nuclear protein isoforms can be produced from this transcript isoform, one in which translation starts at ATG in exon 3 (417 aa), and another with translation starting from ATG in exon 1 (459 aa).
Description Secreted clusterin is produced from the transcript isoform 2. The initial protein precursor, presecretory psCLU (~60 kDa), becomes heavily glycosylated and cleaved in the ER, and the resulting alpha and beta peptide chains are held together by 5 disulfide bonds in the mature secreted heterodimer protein form, sCLU (~75-80 kDa).
Also the nuclear clusterin is first translated as a non-glycosylated protein precursor, pnCLU (~49 kDa), that is then translocated into nucleus. There is evidence of two distinct sized nuclear clusterin proteins (~50 kDa and ~60 kDa, Pajak et al., 2007), that could results from translation started either at ATG present in exon 3 or in exon 1, respectively.
Clusterin proteins have never been crystallized, so the suggested protein structures are based on computational modeling.
Expression Ubiquitous expression in various tissue types.
Localisation The different clusterin protein isoforms localize to different cellular compartments. The nuclear clusterin translocated to nucleus after translation and glycosylation. The secreted clusterin is initially targeted to ER, and the glycosylated protein is eventually secreted. There is also evidence of stress-caused retention of sCLU in the cytosol instead of secretion (Nizard et al., 2007).
Function The functions of clusterin in cells are not fully known. The controversiality of clusterin functions mainly results from the not well-established role of the two different protein isoforms with distinct subcellular localization and somewhat opposing functionalities.
Some known functions include involvement in apoptosis through complexing with Ku70 autoantigen (nCLU, proapoptotic) or interfering with Bax-activation (sCLU, antiapoptotic) (Yang et al., 2000; Leskov et al., 2003; Zhang et al., 2005; Zhang et al., 2006). Clusterin has also been linked to spermatogenesis (Roberts et al., 1991), lipid transport (Jenne et al., 1991; Calero et al., 1994; Gelissen et al., 1998), epithelial cell differentiation (French et al., 1993; Schedin et al., 2000; Kim et al., 2007), TGF-beta signaling through Smad2/Smad3 (Lee et al., 2008), complement activation (Kirszbaum et al., 1992) and tumorigenesis (see below).
Homology Homolog to murine Clu (75%),
Homolog to rat Clu (77%),
Low level homology to human clusterin-like 1 (retinal) (25%).


Somatic 6316delT, an insertion (I)/deletion (D) polymorphism, has been studied in Japanese population (Miwa et al., 2005). D/D genotype was shown to associate with significantly higher total cholesterol levels and low-density lipoprotein (LDL) levels in hypertensive females, and the D allele was an independent predictor of plaque prevalence.
Several SNPs have also been found in CLU-gene, both at coding regions and at UTRs and introns. See SNP database at NCBI.

Implicated in

Entity Prostate cancer
Note Several studies have shown decreased clusterin levels in prostate cancer (Bettuzzi et al., 2000; Scaltriti et al., 2004; Rauhala et al., 2008). On the other hand, there are also reports on increased expression of clusterin in prostate cancer, specifically after androgen ablation therapy (July et al., 2002). These opposing results have been explained by the different isoforms of clusterin, i.e. proapoptotic nCLU being decreased, while antiapoptotic, pro-survival sCLU could be increased. Antisense oligonucleotide (ASO) therapy against clusterin is currently tested in clinical trials to evaluate its efficacy in improving androgen deprivation therapy, as well as to prevent chemoresistance (reviewed in Gleave and Miyake, 2005; Sowery et al., 2008). Data supporting the tumor suppressive role for clusterin include reports on epigenetic regulation of clusterin expression in prostate cancer cell lines (Rauhala et al., 2008) and a recently developed TRAMP/cluKO mouse clusterin knock-out model that develops more poorly differentiated and metastatic tumors (Bettuzzi et al., 2008).
Entity Breast cancer
Note Clusterin expression has been shown to increase in breast cancer (Redondo et al., 2000; Kruger et al., 2007). Similarly to prostate cancer, clusterin ASO therapy is being tested also for breast cancer. Recent results from phase II trial did not support show significant increase in treatment response when docetaxel was combined with anti-clusterin therapy (Chia et al., 2009).
Entity Ovarian cancer
Note Cytoplasmic clusterin expression has been shown to increase in ovarian cancer in stage-specific manner and in response to chemotherapy as a cell-survival promoter (Xie et al., 2007; Wei et al., 2009).
Entity Colorectal cancer
Note Increased cytoplasmic clusterin expression has also been found in colorectal cancers (Xie et al., 2005), and the increased clusterin levels were shown to associate with poor prognosis of stage II colon cancers (Kevans et al., 2009). Clusterin has also been suggested to be a potential stool biomarker for colon cancer screening (Pucci et al., 2009).
Entity Pancreatic cancer
Note In pancreatic cancer the reports of clusterin expression are controversial, with both high and low expression reported for cancers (Xie et al., 2002; Jhala et al., 2006). Lack of clusterin expression was also suggested as a potential discriminator factor for distinguishing pancreatic adenocarcinomas from pancreatic patients from fine-needle aspirations (Jhala et al., 2006). In pancreatic cancers, clusterin expression was associated with longer survival, supporting the idea of clusterin down-regulation in tumor progression (Xie et al., 2002).
Entity Alzheimer's disease
Note Increased clusterin levels are shown in Alzheimer's disease, mostly in astrocytes. Clusterin can bind to amyloid-beta peptides stabilizing them leading to their clearance from the brain. Fibrillized amyloid deposits can be masked by clusterin so that they are not recognized by the host defense system, thus preventing excessive inflammation reaction. Additional protection of neural cells is achieved by inhibiting the complement activation. Furthermore, clusterin can function antiapoptotically through Bax-interference and potentiate survival mediated through TGF-beta signaling. (Reviewed in Nuutinen et al., 2009).
Entity Nephrotic syndrome
Note Clusterin expression is decreased in glomerular diseases causing nephrotic syndrome, with hypercholesterolemia appearing as the unifying feature (Ghiggeri et al., 2002).


The tumor-suppressor activity of Clusterin (CLU) is fully displayed in a novel transgenic model of prostate cancer: the TRAMP/CluKO mice model.
Bettuzzi S, Davalli P, Davoli S, Rizzi F, Belloni L, Pellacani D, Astancolle S, Corti A.
18th Meeting of the European Society for Urological Research (ESUR) 2008.
Functional and structural properties of lipid-associated apolipoprotein J (clusterin).
Calero M, Tokuda T, Rostagno A, Kumar A, Zlokovic B, Frangione B, Ghiso J.
Biochem J. 1999 Dec 1;344 Pt 2:375-83.
PMID 10567218
Phase II trial of OGX-011 in combination with docetaxel in metastatic breast cancer.
Chia S, Dent S, Ellard S, Ellis PM, Vandenberg T, Gelmon K, Powers J, Walsh W, Seymour L, Eisenhauer EA.
Clin Cancer Res. 2009 Jan 15;15(2):708-13.
PMID 19147778
Murine clusterin: molecular cloning and mRNA localization of a gene associated with epithelial differentiation processes during embryogenesis.
French LE, Chonn A, Ducrest D, Baumann B, Belin D, Wohlwend A, Kiss JZ, Sappino AP, Tschopp J, Schifferli JA.
J Cell Biol. 1993 Sep;122(5):1119-30.
PMID 8354695
Apolipoprotein J (clusterin) induces cholesterol export from macrophage-foam cells: a potential anti-atherogenic function?
Gelissen IC, Hochgrebe T, Wilson MR, Easterbrook-Smith SB, Jessup W, Dean RT, Brown AJ.
Biochem J. 1998 Apr 1;331 ( Pt 1):231-7.
PMID 9512484
Depletion of clusterin in renal diseases causing nephrotic syndrome.
Ghiggeri GM, Bruschi M, Candiano G, Rastaldi MP, Scolari F, Passerini P, Musante L, Pertica N, Caridi G, Ferrario F, Perfumo F, Ponticelli C.
Kidney Int. 2002 Dec;62(6):2184-94.
PMID 12427144
Use of antisense oligonucleotides targeting the cytoprotective gene, clusterin, to enhance androgen- and chemo-sensitivity in prostate cancer.
Gleave M, Miyake H.
World J Urol. 2005 Feb;23(1):38-46. Epub 2005 Jan 26. (REVIEW)
PMID 15770517
Clusterin (complement lysis inhibitor) forms a high density lipoprotein complex with apolipoprotein A-I in human plasma.
Jenne DE, Lowin B, Peitsch MC, Bottcher A, Schmitz G, Tschopp J.
J Biol Chem. 1991 Jun 15;266(17):11030-6.
PMID 1904058
Biomarkers in Diagnosis of pancreatic carcinoma in fine-needle aspirates.
Jhala N, Jhala D, Vickers SM, Eltoum I, Batra SK, Manne U, Eloubeidi M, Jones JJ, Grizzle WE.
Am J Clin Pathol. 2006 Oct;126(4):572-9.
PMID 17019794
Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy.
July LV, Akbari M, Zellweger T, Jones EC, Goldenberg SL, Gleave ME.
Prostate. 2002 Feb 15;50(3):179-88.
PMID 11813210
High clusterin expression correlates with a poor outcome in stage II colorectal cancers.
Kevans D, Foley J, Tenniswood M, Sheahan K, Hyland J, O'Donoghue D, Mulcahy H, O'Sullivan J.
Cancer Epidemiol Biomarkers Prev. 2009 Feb;18(2):393-9. Epub 2009 Jan 20.
PMID 19155441
Functional association of the morphogenic factors with the clusterin for the pancreatic beta-cell differentiation.
Kim SY, Lee S, Min BH, Park IS.
Diabetes Res Clin Pract. 2007 Sep;77 Suppl 1:S122-6. Epub 2007 May 23.
PMID 17512083
SP-40,40, a protein involved in the control of the complement pathway, possesses a unique array of disulphide bridges.
Kirszbaum L, Bozas SE, Walker ID.
FEBS Lett. 1992 Feb 3;297(1-2):70-6.
PMID 1551440
Prognostic significance of clusterin immunoreactivity in breast cancer.
Kruger S, Ola V, Fischer D, Feller AC, Friedrich M.
Neoplasma. 2007;54(1):46-50.
PMID 17203891
Clusterin, a novel modulator of TGF-beta signaling, is involved in Smad2/3 stability.
Lee KB, Jeon JH, Choi I, Kwon OY, Yu K, You KH.
Biochem Biophys Res Commun. 2008 Feb 22;366(4):905-9. Epub 2007 Dec 17.
PMID 18082619
Insertion/deletion polymorphism in clusterin gene influences serum lipid levels and carotid intima-media thickness in hypertensive Japanese females.
Miwa Y, Takiuchi S, Kamide K, Yoshii M, Horio T, Tanaka C, Banno M, Miyata T, Sasaguri T, Kawano Y.
Biochem Biophys Res Commun. 2005 Jun 17;331(4):1587-93.
PMID 15883054
Clusterin: A forgotten player in Alzheimer's disease.
Nuutinen T, Suuronen T, Kauppinen A, Salminen A.
Brain Res Rev. 2009 Aug 3. [Epub ahead of print].
PMID 19651157
Clusterin in Stool: A New Biomarker for Colon Cancer Screening?
Pucci S, Bonanno E, Sesti F, Mazzarelli P, Mauriello A, Ricci F, Zoccai GB, Rulli F, Galata G, Spagnoli LG.
Am J Gastroenterol. 2009 Jul 21. [Epub ahead of print].
PMID 19623170
Clusterin is epigenetically regulated in prostate cancer.
Rauhala HE, Porkka KP, Saramaki OR, Tammela TL, Visakorpi T.
Int J Cancer. 2008 Oct 1;123(7):1601-9.
PMID 18649357
Overexpression of clusterin in human breast carcinoma.
Redondo M, Villar E, Torres-Munoz J, Tellez T, Morell M, Petito CK.
Am J Pathol. 2000 Aug;157(2):393-9.
PMID 10934144
Regulation of Sertoli cell transferrin and sulfated glycoprotein-2 messenger ribonucleic acid levels during the restoration of spermatogenesis in the adult hypophysectomized rat.
Roberts KP, Awoniyi CA, Santulli R, Zirkin BR.
Endocrinology. 1991 Dec;129(6):3417-23.
PMID 1954915
Clusterin (SGP-2, ApoJ) expression is downregulated in low- and high-grade human prostate cancer.
Scaltriti M, Brausi M, Amorosi A, Caporali A, D'Arca D, Astancolle S, Corti A, Bettuzzi S.
Int J Cancer. 2004 Jan 1;108(1):23-30.
PMID 14618611
Estrous cycle regulation of mammary epithelial cell proliferation, differentiation, and death in the Sprague-Dawley rat: a model for investigating the role of estrous cycling in mammary carcinogenesis.
Schedin P, Mitrenga T, Kaeck M.
J Mammary Gland Biol Neoplasia. 2000 Apr;5(2):211-25.
PMID 11149574
Clusterin knockdown using the antisense oligonucleotide OGX-011 re-sensitizes docetaxel-refractory prostate cancer PC-3 cells to chemotherapy.
Sowery RD, Hadaschik BA, So AI, Zoubeidi A, Fazli L, Hurtado-Coll A, Gleave ME.
BJU Int. 2008 Aug;102(3):389-97. Epub 2008 Mar 11.
PMID 18336596
Roles of clusterin in progression, chemoresistance and metastasis of human ovarian cancer.
Wei L, Xue T, Wang J, Chen B, Lei Y, Huang Y, Wang H, Xin X.
Int J Cancer. 2009 Aug 15;125(4):791-806.
PMID 19391138
Up-regulated expression of cytoplasmic clusterin in human ovarian carcinoma.
Xie D, Lau SH, Sham JS, Wu QL, Fang Y, Liang LZ, Che LH, Zeng YX, Guan XY.
Cancer. 2005 Jan 15;103(2):277-83.
PMID 15578711
Oncogenic role of clusterin overexpression in multistage colorectal tumorigenesis and progression.
Xie D, Sham JS, Zeng WF, Che LH, Zhang M, Wu HX, Lin HL, Wen JM, Lau SH, Hu L, Guan XY.
World J Gastroenterol. 2005 Jun 7;11(21):3285-9.
PMID 15929184
Expression of clusterin in human pancreatic cancer.
Xie MJ, Motoo Y, Su SB, Mouri H, Ohtsubo K, Matsubara F, Sawabu N.
Pancreas. 2002 Oct;25(3):234-8.
PMID 12370533


This paper should be referenced as such :
Rauhala, H ; Visakorpi, T
CLU (clusterin)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(8):744-748.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  t(1;8)(q42;p21) CLU/AGT
t(8;15)(p21;q22) DIS3L/CLU

External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)1191
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
canSAR (ICR) (select the gene name)
REVIEW articlesautomatic search in PubMed
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