Адам CLU гені: құрылымы, қызметтері және аурулардағы ролі

Protein coding gene in the species Homo sapiens

In humans, clusterin (CLU) is encoded by the CLU gene on chromosome 8. CLU is an extracellular molecular chaperone which binds to misfolded proteins in body fluids to neutralise their toxicity and mediate their cellular uptake by receptor mediated endocytosis. Once internalised by cells, complexes between CLU and misfolded proteins are trafficked to lysosomes where they are degraded. CLU is involved in many diseases including neurodegenerative diseases, cancers, inflammatory diseases, and aging.

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. 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. 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 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.

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. CLU has functional similarities to members of the small heat shock protein family and is thus a molecular chaperone. Unlike most other chaperone proteins, which aid intracellular proteins, CLU is trafficked through the ER/Golgi before normally being secreted. Within the secretory system, CLU has been suggested to facilitate the folding of secreted proteins in an ATP independent way. In addition to Alzheimer's disease, CLU may be involved in other neurodegenerative diseases such as Huntington disease. CLU may promote tumorigenesis by facilitating BAX KLU70 binding and, consequently, preventing BAX from localizing to the outer mitochondrial membrane to stimulate cell death. In clear cell renal cell carcinoma, CLU functions to regulate ERK 1/2 signaling and matrix metallopeptidase 9 expression to promote tumor cell migration, invasion, and metastasis. In epithelial ovarian cancer, CLU has been observed to promote angiogenesis and chemoresistance. Other pathways CLU participates in to downplay apoptosis in tumor cells include the PI3K/AKT/mTOR pathway and NF κB pathway. Unlike most other cancers, which feature upregulated CLU levels to enhance tumor cell survival, 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. 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 was tested in phase III trials. CLU activity is also involved in infectious diseases, such as hepatitis C. CLU is induced by the stress of hepatitis C viral infection, which disrupts glucose regulation. The chaperone protein then aids hepatitis C viral assembly by stabilizing its core and NS5A units. In addition to the above diseases, CLU has been linked to other conditions resulting from oxidative damage, including aging, glomerulonephritis, atherosclerosis, and myocardial infarction.

CLU has been shown to interact with many different protein ligands and several cell receptors.