CLU

Official Full Name

clusterin

Organism

Homo sapiens

GeneID

1191

Background

The protein encoded by this gene is a secreted chaperone that can under some stress conditions also be found in the cell cytosol. It has been suggested to be involved in several basic biological events such as cell death, tumor progression, and neurodegenerative disorders. Alternate splicing results in both coding and non-coding variants.[provided by RefSeq, May 2011]

Synonyms

CLI; AAG4; APOJ; CLU1; CLU2; KUB1; SGP2; APO-J; SGP-2; SP-40; TRPM2; TRPM-2; NA1/NA2;

Bio Chemical Class

mRNA target

Protein Sequence

MMKTLLLFVGLLLTWESGQVLGDQTVSDNELQEMSNQGSKYVNKEIQNAVNGVKQIKTLIEKTNEERKTLLSNLEEAKKKKEDALNETRESETKLKELPGVCNETMMALWEECKPCLKQTCMKFYARVCRSGSGLVGRQLEEFLNQSSPFYFWMNGDRIDSLLENDRQQTHMLDVMQDHFSRASSIIDELFQDRFFTREPQDTYHYLPFSLPHRRPHFFFPKSRIVRSLMPFSPYEPLNFHAMFQPFLEMIHEAQQAMDIHFHSPAFQHPPTEFIREGDDDRTVCREIRHNSTGCLRMKDQCDKCREILSVDCSTNNPSQAKLRRELDESLQVAERLTRKYNELLKSYQWKMLNTSSLLEQLNEQFNWVSRLANLTQGEDQYYLRVTTVASHTSDSDVPSGVTEVVVKLFDSDPITVTVPVEVSRKNPKFMETVAEKALQEYRKKHREE

Open

Disease

Breast cancer, Lung cancer, Prostate cancer

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

The CLU gene is located on certain human chromosomes and encodes clusterin. It consists of 9 exons and 8 introns, producing different protein isoforms, including secreted CLU (sCLU) and nuclear CLU (nCLU). These isoforms are generated through selective splicing, participating in various physiological cellular processes. Secreted CLU primarily exists extracellularly, acting as a molecular chaperone to aid protein folding and prevent aggregation, whereas nuclear CLU functions in the cell nucleus to regulate the cell cycle and induce apoptosis.

CLU gene expression plays a significant role in various biological processes, particularly in stress response, lipid metabolism, immune modulation, and apoptosis. Under stress conditions, it effectively maintains intracellular protein stability, preventing harmful protein aggregation.

Functions of CLU Protein

As a multifunctional protein, clusterin's roles in cellular physiological and pathological processes are extensive. It is best known for its dual role in cell protection and apoptosis regulation. Secreted CLU (sCLU) is considered a molecular chaperone, protecting cells from stress-induced damage primarily by preventing protein misfolding and aggregation. It stabilizes unfolded proteins and prevents their aggregation under stress conditions. Studies show sCLU inhibits the aggregation of plasma proteins under stress, playing a critical role in inhibiting amyloid aggregation.

Figure 1 illustrates clusterin molecular chaperone activity, where, under stress, it dissociates oligomers to release active subunits that bind and stabilize misfolded proteins, preventing aggregation while other chaperones attempt refolding. Figure 1. Representation of clusterin's molecular chaperone activity. (Spatharas PM, et al., 2022)

CLU interacts intracellularly with other proteins like HSPA8 (heat shock protein 70) and HSPA5, therefore preserving intracellular protein stability. It controls ubiquitination therefore promoting the breakdown of extraneous proteins and preventing endoplasmic reticulum stress-induced cell death.

Furthermore, nuclear and secreted CLU have opposite functions in the control of death. Whereas nuclear CLU causes cell death by controlling the cell cycle and causing apoptosis, sCLU reduces death by shielding cells from outside stimuli. In various stress responses, CLU's action is considered a cellular protective mechanism, balancing cell survival and death under damage conditions.

Relationship Between CLU and Cancer

Recent studies have focused on CLU in cancer. As a molecular chaperone, sCLU enhances tumor cell survival, leading to resistance against chemotherapy and radiotherapy. In various tumor types, CLU expression levels and isoform changes are closely associated with tumor initiation, progression, and metastasis. Overexpression of sCLU correlates with tumor cell invasiveness, migratory ability, and chemotherapy resistance, making it an important biomarker for cancer prognosis.

In some cancers, sCLU expression levels are closely linked to patient prognosis. For example, in colorectal cancer patients, CLU expression is associated with patient survival, with sCLU overexpression usually indicating poorer prognosis. Similar studies indicate that high sCLU expression is linked to worsening and resistance in cancers such as ovarian, breast, and prostate cancers.

Nuclear CLU (nCLU), however, promotes cell death in some tumor types. In prostate cancer, nCLU expression helps control tumor progression by promoting apoptosis and inhibiting metastasis. Therefore, nuclear CLU can be a potential target in cancer treatment; increasing nCLU expression or inhibiting sCLU may enhance cancer therapy effectiveness.

CLU as a Therapeutic Target

CLU's dual role in cancer makes it a promising therapeutic target. Using an antisense oligonucleotide against CLU, OGX-011, may significantly reduce CLU expression and increase cancer cell susceptibility to radiation and chemotherapy, according to clinical experiments. Studies have shown that chemotherapy with OGX-011 greatly increases therapeutic effectiveness.

Furthermore, a possible biomarker for early cancer diagnosis and prognosis evaluation is CLU's differential expression in tumors and its link with tumor development. Research advances may find CLU as a novel therapeutic target, particularly in treating advanced malignancies and chemotherapy-resistant tumors, therefore providing patients with improved prognoses with focused CLU treatment.

CLU's Role in Other Diseases

Beyond cancer, CLU plays a crucial role in various other diseases. In neurodegenerative diseases like Alzheimer's, CLU is considered protective, actively inhibiting neuronal death and alleviating nerve damage. Loss or dysfunction of CLU may contribute to Alzheimer's onset and progression.

In cardiovascular and metabolic diseases, CLU also demonstrates significant biological importance. Its roles in lipid metabolism, oxidative stress response, and immune modulation suggest potential therapeutic value in diseases such as atherosclerosis, diabetes, and obesity.

References:

Spatharas PM, Nasi GI, et al. Clusterin in Alzheimer's disease: An amyloidogenic inhibitor of amyloid formation? Biochim Biophys Acta Mol Basis Dis. 2022;1868(7):166384.
Téllez T, Martin-García D, Redondo M, García-Aranda M. Clusterin Expression in Colorectal Carcinomas. Int J Mol Sci. 2023 Sep 27;24(19):14641.

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