CLU (clusterin)

2009-10-01   Hanna Rauhala , Tapio Visakorpi 

Institute of Medical Technology, University of Tampere, Tampere University Hospital, Tampere, Finland

Identity

HGNC
LOCATION
8p21.1
LOCUSID
ALIAS
AAG4,APO-J,APOJ,CLI,CLU1,CLU2,KUB1,NA1/NA2,SGP-2,SGP2,SP-40,TRPM-2,TRPM2
FUSION GENES

DNA/RNA

Atlas Image
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.

Proteins

Atlas Image
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%).

Mutations

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 name
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 name
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 name
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 name
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 name
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 name
Alzheimers disease
Note
Increased clusterin levels are shown in Alzheimers 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 name
Nephrotic syndrome
Note
Clusterin expression is decreased in glomerular diseases causing nephrotic syndrome, with hypercholesterolemia appearing as the unifying feature (Ghiggeri et al., 2002).

Bibliography

Pubmed IDLast YearTitleAuthors
105672181999Functional and structural properties of lipid-associated apolipoprotein J (clusterin).Calero M et al
191477782009Phase II trial of OGX-011 in combination with docetaxel in metastatic breast cancer.Chia S et al
83546951993Murine clusterin: molecular cloning and mRNA localization of a gene associated with epithelial differentiation processes during embryogenesis.French LE et al
95124841998Apolipoprotein J (clusterin) induces cholesterol export from macrophage-foam cells: a potential anti-atherogenic function?Gelissen IC et al
124271442002Depletion of clusterin in renal diseases causing nephrotic syndrome.Ghiggeri GM et al
157705172005Use of antisense oligonucleotides targeting the cytoprotective gene, clusterin, to enhance androgen- and chemo-sensitivity in prostate cancer.Gleave M et al
19040581991Clusterin (complement lysis inhibitor) forms a high density lipoprotein complex with apolipoprotein A-I in human plasma.Jenne DE et al
170197942006Biomarkers in Diagnosis of pancreatic carcinoma in fine-needle aspirates.Jhala N et al
118132102002Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy.July LV et al
191554412009High clusterin expression correlates with a poor outcome in stage II colorectal cancers.Kevans D et al
175120832007Functional association of the morphogenic factors with the clusterin for the pancreatic beta-cell differentiation.Kim SY et al
15514401992SP-40,40, a protein involved in the control of the complement pathway, possesses a unique array of disulphide bridges.Kirszbaum L et al
172038912007Prognostic significance of clusterin immunoreactivity in breast cancer.Krüger S et al
180826192008Clusterin, a novel modulator of TGF-beta signaling, is involved in Smad2/3 stability.Lee KB et al
158830542005Insertion/deletion polymorphism in clusterin gene influences serum lipid levels and carotid intima-media thickness in hypertensive Japanese females.Miwa Y et al
196511572009Clusterin: a forgotten player in Alzheimer's disease.Nuutinen T et al
196231702009Clusterin in stool: a new biomarker for colon cancer screening?Pucci S et al
186493572008Clusterin is epigenetically regulated in prostate cancer.Rauhala HE et al
109341442000Overexpression of clusterin in human breast carcinoma.Redondo M et al
19549151991Regulation of Sertoli cell transferrin and sulfated glycoprotein-2 messenger ribonucleic acid levels during the restoration of spermatogenesis in the adult hypophysectomized rat.Roberts KP et al
146186112004Clusterin (SGP-2, ApoJ) expression is downregulated in low- and high-grade human prostate cancer.Scaltriti M et al
111495742000Estrous 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 et al
183365962008Clusterin knockdown using the antisense oligonucleotide OGX-011 re-sensitizes docetaxel-refractory prostate cancer PC-3 cells to chemotherapy.Sowery RD et al
193911382009Roles of clusterin in progression, chemoresistance and metastasis of human ovarian cancer.Wei L et al
155787112005Up-regulated expression of cytoplasmic clusterin in human ovarian carcinoma.Xie D et al
159291842005Oncogenic role of clusterin overexpression in multistage colorectal tumorigenesis and progression.Xie D et al
123705332002Expression of clusterin in human pancreatic cancer.Xie MJ et al

Other Information

Locus ID:

NCBI: 1191
MIM: 185430
HGNC: 2095
Ensembl: ENSG00000120885

Variants:

dbSNP: 1191
ClinVar: 1191
TCGA: ENSG00000120885
COSMIC: CLU

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000120885ENST00000316403P10909
ENSG00000120885ENST00000405140P10909
ENSG00000120885ENST00000519472E5RG36
ENSG00000120885ENST00000519742E5RJZ5
ENSG00000120885ENST00000520491E5RH61
ENSG00000120885ENST00000520796E7ERK6
ENSG00000120885ENST00000521770H0YAS8
ENSG00000120885ENST00000522098H0YC35
ENSG00000120885ENST00000522238E5RJD6
ENSG00000120885ENST00000522413E5RGB0
ENSG00000120885ENST00000523396E5RG36
ENSG00000120885ENST00000523500P10909
ENSG00000120885ENST00000523589E7ETB4
ENSG00000120885ENST00000560566H0YLK8

Expression (GTEx)

0
500
1000
1500
2000

Pathways

PathwaySourceExternal ID
Complement and coagulation cascadesKEGGko04610
Complement and coagulation cascadesKEGGhsa04610
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Complement cascadeREACTOMER-HSA-166658
Terminal pathway of complementREACTOMER-HSA-166665
HemostasisREACTOMER-HSA-109582
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
Response to elevated platelet cytosolic Ca2+REACTOMER-HSA-76005
Platelet degranulationREACTOMER-HSA-114608
Antimicrobial peptidesREACTOMER-HSA-6803157

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
197349022009Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.990
197349022009Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.990
197349032009Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease.889
197349032009Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease.889
204606222010Genome-wide analysis of genetic loci associated with Alzheimer disease.461
185420502008TRPM2-mediated Ca2+influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration.194
206970302010Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes.158
206970302010Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes.158
161136782005Clusterin inhibits apoptosis by interacting with activated Bax.125
206034552010Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease.120

Citation

Hanna Rauhala ; Tapio Visakorpi

CLU (clusterin)

Atlas Genet Cytogenet Oncol Haematol. 2009-10-01

Online version: http://atlasgeneticsoncology.org/gene/40107/clu-(clusterin)