Clusterin

Clusterin
Identifiers
SymbolsCLU ; APO-J; APOJ; CLI; CLU1; CLU2; KUB1; NA1/NA2; SGP-2; SGP2; SP-40; TRPM-2; TRPM2
External IDsOMIM: 185430 MGI: 88423 HomoloGene: 1382 ChEMBL: 1741303 GeneCards: CLU Gene
Orthologs
SpeciesHumanMouse
Entrez119112759
EnsemblENSG00000120885ENSMUSG00000022037
UniProtP10909Q06890
RefSeq (mRNA)NM_001831NM_013492
RefSeq (protein)NP_001822NP_038520
Location (UCSC)Chr 8:
27.45 – 27.47 Mb		Chr 14:
65.97 – 65.98 Mb
PubMed search

Clusterin (apolipoprotein J) is a 75 - 80 kDa disulfide-linked heterodimeric protein associated with the clearance of cellular debris and apoptosis.[1] In humans, clusterin is encoded by the CLU gene.[2]

This protein has several synonyms: dimeric acidic glycoprotein (DAG protein), testosterone repressed prostate message-2 (TRPM-2), sulfated glycoprotein-2 (SGP-2) and complement lysis inhibitor (CLI).

Genomics

Clusterin was first identified in ram rete testis fluid where it showed signs of clustering with rat sertoli cells and erythrocytes, hence its name.[3]

In humans the gene is encoded on chromosome 8 (8p21) and is highly conserved between species (70-80% homology). It is expressed in most mammalian tissues and can be found in blood plasma, milk, urine, cerebrospinal fluid and semen. A number of proteins have been found to affect its expression including Egr-1, members from the AP-1 complex, HSF1/2, Cdx1/2 and B-Myb.

Molecular biology

The protein itself is a disulfide-linked heterodimeric protein containing about 30% of N-linked carbohydrate rich in sialic acid. Truncated forms targeted to the nucleus have also been identified. The precursor polypeptide chain is cleaved proteolytically to remove the 22 amino acid secretory signal peptide and subsequently between residues 227/228 to generate the alpha and beta chains. These are assembled in an anti-parallel fashion to give a heterodimeric molecule in which the cysteine-rich centers are linked by five disulfide bridges and are flanked by two predicted coiled-coil alpha-helices and three predicted amphipathic alpha-helices.

The mature protein appears as a ≈40 kDa smear on immunoblots from reducing SDS-PAGE. The precursor form appears as a 60 kDa protein.

The protein has been implicated in a variety of activities including programmed cell death, regulation of complement mediated cell lysis, membrane recycling, cell-cell adhesion and src induced transformation. As a part of the attack complex of complement, it acts as a complement inhibitor.

It is able to bind and form complexes with numerous partners such as immunoglobulins, lipids, heparin, bacteria, complement components, paraoxonase, beta amyloid, leptin and others. Clusterin has been ascribed a plethora of functions such as phagocyte recruitment, aggregation induction, complement attack prevention, apoptosis inhibition, membrane remodelling, lipid transport, hormone transport and/or scavenging and matrix metalloproteinase inhibition.

Clinical associations

Two independent genome-wide association studies[4][5] 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,[6] and that clusterin levels in blood correlate with faster cognitive decline in individuals with Alzheimer's disease,[7] but have not found that clusterin levels predicted the onset of Alzheimer's disease.

There are two isoforms (1 and 2) with antagonistic actions regarding apoptosis. Clusterin is implicated in a number of biological processes, including lipid transport, membrane recycling, cell adhesion, programmed cell death, and complement cascade, representing a truly multifunctional protein. Isoform 2 is overexpressed under cellular stress conditions and protects cells from apoptosis by impeding Bax actions on the mitochondrial membrane and exerts other protumor activities, like phosphatidylinositol 3-kinase/protein kinase B pathway activation, modulation of extracellular signal-regulated kinase 1/2 signaling and matrix metallopeptidase-9 expression, increased angiogenesis, modulation of the nuclear factor kappa B pathway, among others.<http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964162/>

References

  1. ↑ Jones SE, Jomary C (May 2002). "Clusterin". Int. J. Biochem. Cell Biol. 34 (5): 427–431. doi:10.1016/S1357-2725(01)00155-8. PMID 11906815.
  2. ↑ "Entrez Gene: clusterin".
  3. ↑ Fritz IB, Burdzy K, Sétchell B, Blaschuk O (June 1983). "Ram rete testis fluid contains a protein (clusterin) which influences cell-cell interactions in vitro". Biol. Reprod. 28 (5): 1173–1188. doi:10.1095/biolreprod28.5.1173. PMID 6871313.
  4. ↑ Harold D; Abraham R; Hollingworth P et al. (September 2009). "Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease". Nat. Genet. 41 (10): 1088–1093. doi:10.1038/ng.440. PMC 2845877. PMID 19734902. Lay summary – TIME Magazine (2009-09-06).
  5. ↑ Lambert JC; Heath S; Even G et al. (September 2009). "Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease". Nat. Genet. 41 (10): 1094–1099. doi:10.1038/ng.439. PMID 19734903.
  6. ↑ Schrijvers EM et al. (September 2011). "Plasma clusterin and the risk of Alzheimer disease". JAMA 305 (13): 1322–1326. doi:10.1001/jama.2011.381. PMID 21467285.
  7. ↑ "Plasma Protein Appears to Be Associated With Development and Severity of Alzheimer's Disease". 2010.

8.- Koltai T. Clusterin a key player in cancer chemoresistance and its inhibition. 2014 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964162/

Further reading

  • Krumbiegel M; Pasutto F; Mardin CY et al. (2009). "Exploring functional candidate genes for genetic association in german patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma". Invest. Ophthalmol. Vis. Sci. 50 (6): 2796–2801. doi:10.1167/iovs.08-2339. PMID 19182256.
  • Cerhan JR; Novak AJ; Fredericksen ZS et al. (2009). "Risk of non-Hodgkin lymphoma in association with germline variation in complement genes". Br. J. Haematol. 145 (5): 614–623. doi:10.1111/j.1365-2141.2009.07675.x. PMC 2820509. PMID 19344414.
  • Trougakos IP, Gonos ES (2002). "Clusterin/apolipoprotein J in human aging and cancer". Int. J. Biochem. Cell Biol. 34 (11): 1430–1448. doi:10.1016/S1357-2725(02)00041-9. PMID 12200037.
  • Jenne DE, Tschopp J (1992). "Clusterin: the intriguing guises of a widely expressed glycoprotein". Trends Biochem. Sci. 17 (4): 154–159. doi:10.1016/0968-0004(92)90325-4. PMID 1585460.
  • StÃ¥hl AL; Kristoffersson A; Olin AI et al. (2009). "A novel mutation in the complement regulator clusterin in recurrent hemolytic uremic syndrome". Mol. Immunol. 46 (11–12): 2236–2243. doi:10.1016/j.molimm.2009.04.012. PMID 19446882.
  • Balantinou E; Trougakos IP; Chondrogianni N et al. (2009). "Transcriptional and posttranslational regulation of clusterin by the two main cellular proteolytic pathways". Free Radic. Biol. Med. 46 (9): 1267–1274. doi:10.1016/j.freeradbiomed.2009.01.025. PMID 19353783.
  • Wei L; Xue T; Wang J et al. (2009). "Roles of clusterin in progression, chemoresistance and metastasis of human ovarian cancer". Int. J. Cancer 125 (4): 791–806. doi:10.1002/ijc.24316. PMID 19391138.
  • Chou TY; Chen WC; Lee AC et al. (2009). "Clusterin silencing in human lung adenocarcinoma cells induces a mesenchymal-to-epithelial transition through modulating the ERK/Slug pathway". Cell. Signal. 21 (5): 704–711. doi:10.1016/j.cellsig.2009.01.008. PMID 19166932.
  • Olsen SH, Ma L, Schnitzer B, Fullen DR (2009). "Clusterin expression in cutaneous CD30-positive lymphoproliferative disorders and their histologic simulants". J. Cutan. Pathol. 36 (3): 302–307. doi:10.1111/j.1600-0560.2008.01036.x. PMID 19220628.
  • Aigelsreiter A; Janig E; Sostaric J et al. (2009). "Clusterin expression in cholestasis, hepatocellular carcinoma and liver fibrosis". Histopathology 54 (5): 561–570. doi:10.1111/j.1365-2559.2009.03258.x. PMID 19413638.
  • Pucci S; Paola M; Fabiola S et al. (2009). "Interleukin-6 affects cell death escaping mechanisms acting on Bax-Ku70-Clusterin interactions in human colon cancer progression". Cell Cycle 8 (3): 473–81. doi:10.4161/cc.8.3.7652. PMC 2853871. PMID 19177010.
  • Trougakos IP; Lourda M; Antonelou MH et al. (2009). "Intracellular clusterin inhibits mitochondrial apoptosis by suppressing p53-activating stress signals and stabilizing the cytosolic Ku70-Bax protein complex". Clin. Cancer Res. 15 (1): 48–59. doi:10.1158/1078-0432.CCR-08-1805. PMID 19118032.
  • Boland JM, Folpe AL, Hornick JL, Grogg KL (2009). "Clusterin is expressed in normal synoviocytes and in tenosynovial giant cell tumors of localized and diffuse types: diagnostic and histogenetic implications". Am. J. Surg. Pathol. 33 (8): 1225–1229. doi:10.1097/PAS.0b013e3181a6d86f. PMID 19542874.
  • Chandra P; Plaza JA; Zuo Z et al. (2009). "Clusterin expression correlates with stage and presence of large cells in mycosis fungoides". Am. J. Clin. Pathol. 131 (4): 511–515. doi:10.1309/AJCPH43ZDVLSOSNB. PMID 19289586.
  • Rizzi F, Caccamo AE, Belloni L, Bettuzzi S (2009). "Clusterin is a short half-life, poly-ubiquitinated protein, which controls the fate of prostate cancer cells". J. Cell. Physiol. 219 (2): 314–323. doi:10.1002/jcp.21671. PMID 19137541.
  • Liao FT; Lee YJ; Ko JL et al. (2009). "Hepatitis delta virus epigenetically enhances clusterin expression via histone acetylation in human hepatocellular carcinoma cells". J. Gen. Virol. 90 (Pt 5): 1124–1134. doi:10.1099/vir.0.007211-0. PMID 19264665.
  • Shannan B; Seifert M; Boothman DA et al. (2006). "Clusterin and DNA repair: a new function in cancer for a key player in apoptosis and cell cycle control". J. Mol. Histol. 37 (5–7): 183–188. doi:10.1007/s10735-006-9052-7. PMID 17048076.
  • Shannan B; Seifert M; Leskov K et al. (2006). "Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer". Cell Death Differ. 13 (1): 12–19. doi:10.1038/sj.cdd.4401779. PMID 16179938.
  • Otowa T; Yoshida E; Sugaya N et al. (2009). "Genome-wide association study of panic disorder in the Japanese population". J. Hum. Genet. 54 (2): 122–126. doi:10.1038/jhg.2008.17. PMID 19165232.

External links