death. p53 may also transcriptionally repress secretory CLU to further promote the proapoptotic cascade. Clinical associations Two independent genome-wide association studies 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, and that clusterin levels in blood correlate with faster cognitive decline in individuals with Alzheimer's disease, but have not found that clusterin levels predicted the onset of Alzheimer's disease. In addition to Alzheimer's disease, CLU is 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 is currently 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. CLU expression in the kidney also plays a role in renal diseases, such as nephropathic cystinosis, which is a major cause of Fanconi syndrome. In addition to the above diseases, CLU has been linked to other conditions resulting from oxidative damage, including aging, glomerulonephritis, atherosclerosis, and myocardial infarction. Interactions CLU has been shown to interact with Ku70. References Further reading