Clusterin
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| Location (UCSC) | Chr 8: 27.6 – 27.61 Mb | Chr 14: 66.21 – 66.22 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
In humans, clusterin (CLU) is encoded by the CLU
Structure
The CLU gene contains nine exons and a variety of mRNA isoforms can be detected, although most of these are only ever expressed at very low levels (< 0.3% of the total). The full-length mRNA encoding the secreted isoform is by far the dominant species transcribed. [10] Secreted CLU (apolipoprotein J) is an approximately 60 kDa disulfide-linked heterodimeric glycoprotein which migrates in SDS-PAGE with an apparent molecular mass of 75-80 kDa. [11] Mature CLU is composed of disulfide-linked α- and β-chains. Although multiple previous publications proposed the existence of N-terminally truncated CLU protein isoforms in different cell compartments, recent work has highlighted the lack of direct evidence for this [12] and shown that the full-length CLU polypeptide, with variable levels of glycosylation (and hence variable apparent mass), can translocate from the ER/Golgi to the cytosol and nucleus during stress.[13]
Function
Clusterin was first identified in ram rete testis fluid where it was shown to elicit in vitro clustering of rat Sertoli cells and erythrocytes, hence its name.[14]
CLU has functional similarities to members of the small
mitochondrial dysfunction and cell death. p53 may also transcriptionally repress secretory CLU to further promote the proapoptotic cascade.[7]
Clinical associations
Two independent
Huntington disease.[8]
CLU may promote tumorigenesis by facilitating BAX-KLU70 binding and, consequently, preventing BAX from localizing to the
testicular seminoma features downregulated CLU levels, allowing for increased sensitivity to chemotherapy treatments. Other cancers CLU has been implicated in include breast cancer, pancreatic cancer, hepatocellular carcinoma, and melanoma
.
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.
CLU activity is also involved in infectious diseases, such as
viral infection, which disrupts glucose regulation. The chaperone protein then aids hepatitis C viral assembly by stabilizing its core and NS5A units.[9] In addition to the above diseases, CLU has been linked to other conditions resulting from oxidative damage, including aging, glomerulonephritis, atherosclerosis, and myocardial infarction. [9]
Interactions
CLU has been shown to interact with many different protein ligands and several cell receptors. [12]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000120885 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022037 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: clusterin".
- PMID 23350744.
- ^ PMID 24672247.
- ^ PMID 25071085.
- ^ PMID 24996046.
- PMID 24073260.
- PMID 9336835.
- ^ S2CID 231897964.
- PMID 37660295.
- PMID 6871313.
- PMID 19734902.
- Alice Park (2009-09-07). "Breakthrough Discoveries of Alzheimer's Genes". Time. Archived from the original on 2009-09-09.
- S2CID 24530130.
- S2CID 36026598.
- ^ "Plasma Protein Appears to Be Associated With Development and Severity of Alzheimer's Disease". 2010.
Further reading
- 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. PMID 19182256.
- Cerhan JR, Novak AJ, Fredericksen ZS, Wang AH, Liebow M, Call TG, Dogan A, Witzig TE, Ansell SM, Habermann TM, Kay NE, Slager SL (Jun 2009). "Risk of non-Hodgkin lymphoma in association with germline variation in complement genes". British Journal of Haematology. 145 (5): 614–23. PMID 19344414.
- 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. PMID 12200037.
- Jenne DE, Tschopp J (Apr 1992). "Clusterin: the intriguing guises of a widely expressed glycoprotein". Trends in Biochemical Sciences. 17 (4): 154–9. PMID 1585460.
- 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. PMID 19446882.
- 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. PMID 19353783.
- 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. S2CID 23162609.
- 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. PMID 19166932.
- Olsen SH, Ma L, Schnitzer B, Fullen DR (Mar 2009). "Clusterin expression in cutaneous CD30-positive lymphoproliferative disorders and their histologic simulants" (PDF). Journal of Cutaneous Pathology. 36 (3): 302–7. S2CID 8915250.
- 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. S2CID 21277859.
- Pucci S, Mazzarelli P, Paola M, Sesti F, Fabiola S, Boothman DA, David BA, Spagnoli LG, Luigi SG (Feb 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. PMID 19177010.
- 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. PMID 19118032.
- 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. S2CID 24444024.
- 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. PMID 19289586.
- 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. S2CID 206047289.
- 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. PMID 19264665.
- 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. S2CID 20041580.
- 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. PMID 16179938.
- 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. PMID 19165232.
- 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 of Molecular Histology. 39 (6): 605–16. S2CID 11598911.
External links
- Clusterin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Apolipoproteins and Applied Research