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PubMed2004

Clusterin, a marker for anaplastic large cell lymphoma immunohistochemical profile in hematopoietic and nonhematopoietic malignant neoplasms.

We evaluated the immunohistochemical staining profile of clusterin in paraffin sections of 143 neoplasms (non-Hodgkin lymphoma, 83, including 41 anaplastic large cell lymphomas [ALCLs]; Hodgkin lymphoma, 17; primary and metastatic carcinoma, 30; and other neoplasms, 13). In 40 of 41 ALCLs (34 systemic, 7 cutaneous), neoplastic cells revealed clusterin reactivity characterized by a Golgi staining pattern. The proportion of reactive cells varied with more than 25% positive cells in the majority of cases. In 7 non-Hodgkin lymphomas of other types, fine cytoplasmic (3 cases) or strong membranous reactivity (4 cases) was observed for clusterin. In Hodgkin lymphoma, rare Reed-Sternberg cells exhibited focal cytoplasmic or membranous clusterin positivity. In the nonhematopoietic neoplasms, a Golgi staining pattern was apparent in only 2 cases, 1 lobular carcinoma of the breast and 1 poorly differentiated colonic carcinoma; however, cytoplasmic reactivity was noted in 12 of 30 carcinomas and 1 of 5 neuroendocrine neoplasms. A Golgi pattern of reactivity for clusterin seems highly characteristic of ALCL among hematopoietic neoplasms, but also might be observed in rare nonhematopoietic tumors, necessitating the use of a broad immunohistochemical panel for evaluation of poorly differentiated neoplasms of indeterminate derivation.

Adolescent↗
PubMed1992

Expression of the clusterin gene in the tissues of Booroola sheep which were homozygotes or non-carriers of the fecundity gene FecB.

Clusterin or sulphated glycoprotein-2 is a major component of the rete testis fluid, synthesized by the rete testis epithelial cells and Sertoli cells. Differences in the two-dimensional polyacrylamide gel electrophoresis pattern of clusterin-like proteins have been reported in rete testis fluid from Booroola rams carrying the fecundity gene FecB, when compared with that from non-carrier rams. In order to determine whether the FecB gene influences the expression of the clusterin gene, we used a rat clusterin cRNA probe to investigate mRNA species in the tissues of homozygous (BB) or non-carrier (++) Booroola sheep. Northern blots of polyadenylated RNA showed hybridization to the cRNA probe in the testis, ovarian follicles, corpora lutea and stroma, pituitary and liver. A major mRNA transcript was observed at 2.3 kb and a minor transcript in some tissues at 0.8 kb. Densitometry of the autoradiographs revealed no FecB-specific differences in the densities of the hybridization signals from ++ and BB testis or ovarian follicle, corpora lutea or stromal RNA. We conclude that the gene for ovine clusterin is expressed widely in the tissues of sheep and that its expression is not affected by the presence of the FecB gene.

Animals↗
PubMed1992

Measurement of urinary clusterin as an index of nephrotoxicity.

Measurements of tissue immunoassayable clusterin, a protein associated with programmed cell death and tissue reorganization, were performed in rats treated with nephrotoxic doses of gentamicin sulfate. Adult Lewis rats were treated with 100 mg/kg/day of gentamicin sulfate for 12 days. Urine, serum, and tissue levels of clusterin protein were measured, as were urinary N-acetyl beta-glucosaminidase (NAG) and serum creatinine levels. Induction of renal injury by gentamicin was detectable within 4 days by increased levels of urinary N-acetyl beta-glucosaminidase (from 280 +/- 66 (mean +/- SD) to 910 +/- 210 nmol/mg creatinine), and within 9 days of initiating gentamicin treatment by increased serum creatinine (from 0.5 +/- 0.1 to 1.2 +/- 0.4 mg/dl). Paralleling these changes, renal, urinary, and serum levels of clusterin increased 10-, 116-, and 3-fold (P less than 0.05). Treatment with gentamicin sulfate did not increase clusterin levels in the seminal vesicle, ventral prostate, testis, or epididymis. The measurement of urinary or serum clusterin may play a role in the early detection of renal injury.

Acetylglucosaminidase↗
PubMed1993

Urinary clusterin in chronic nephrotoxicity in the rat.

The excretion of clusterin was compared with that of N-acetyl-beta-glucosaminidase (NAG) in rats given gentamicin daily for 2 months to determine whether clusterin excretion stays elevated after NAG excretion falls during chronic gentamicin administration. Clusterin was measured by radioimmunoassay and NAG by the hydrolysis of 4-methylumbelliferyl-N-acetyl-beta-D-glucosaminide. Gentamicin at 110 mg/kg was given daily for 44 days and thereafter, at 90 mg/kg daily. The excretion rate of both proteins rose rapidly, peaked, and then declined; however, the clusterin values stayed significantly above control values for the entire study, whereas NAG values were close to normal during the last 10 days, even though tubulointerstitial disease was active at that time. For this reason, the further evaluation of clusterin as a marker of renal tubular cell injury or death is warranted.

Acetylglucosaminidase↗
PubMed2000

Localisation of clusterin in normal human sperm by immunogold electron microscopy.

In the human male reproductive tract, two forms of clusterin have been detected: the conventional heterodimeric form and a novel acrosomal form. On human sperm the novel form of clusterin is present in the acrosomal region of acrosome intact sperm only. The aim of this study was to determine the site of localisation of the acrosomal form of clusterin using immunogold electron microscopy on normal human sperm. Using the E5 anticlusterin mAb and a preembedding technique, acrosomal clusterin was localised in the acrosomal contents. Immunogold particles were detected on ethanol fixed spermatozoa that were subjected to Triton X-100 permeabilisation treatment. These sperm had lost their plasmalemma and outer acrosomal membrane. Specific immunogold labeling was present over the surface mainly of the acrosomal contents exposed by the loss of the plasma-lemma and outer acrosomal membrane. Immunogold particles were also detected in the equatorial segment of the sperm. These data confirm that the acrosomal form of clusterin is associated with the contents of the acrosome.

Acrosome↗
PubMed2006

Expression of clusterin, XIAP and survivin, and their changes by camptothecin (CPT) treatment in CPT-resistant PC-3 and CPT-sensitive LNCaP cells.

AIM: Clusterin and IAPs (inhibitor of apoptosis proteins), such as survivin and XIAP, are known to be related to chemo-resistance in several cancer cells. In the current study, we investigated their expression levels in human prostate cancer cell lines, LNCaP and PC-3 which are sensitive and resistant to camptothecin (CPT), topoisomerase I inhibitor, respectively. METHODS: LNCaP and PC-3 cells were cultured in the presence of CPT, cell death was evaluated using Hoechst 33342 and propidium iodide (PI) double staining. The expression of clusterin, XIAP and survivin on mRNA and protein levels was investigated by semi-quantitative RT-PCR and Western blotting, respectively. RESULTS: Our data showed that 24 h treatment of LNCaP cells with 0.5 and 3.0 microM CPT resulted in higher number of apoptotic cells, than that in PC-3 cells. Western blot analysis revealed that the clusterin level in PC-3 cells was 5-fold higher than that in LNCaP cells. In contrast, XIAP expression level in PC-3 cells was lower than that in LNCaP cells, and survivin levels were similar in these two cell lines. Treatment with 0.5 and 3.0 microM CPT resulted in the reduced survivin and XIAP expression in both cell lines, while clusterin expression remained unchanged in LNCaP cells, but was increased in PC-3 cells. CONCLUSION: The results suggest that clusterin may take a greater part in CPT-resistance than survivin and XIAP in PC-3 cells.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Tamoxifen exerts agonistic effects on clusterin and complement C3 gene expression in RUCA-I primary xenografts and metastases but not normal uterus.

Tamoxifen is the most widely prescribed anti-neoplastic drug for the treatment of both localized and metastatic breast cancer. It is also the prototype for a class of drugs that are referred to as selective estrogen receptor modifiers (SERMs), most of which have both estrogenic and anti-estrogenic activity in estrogen target tissues including the breast and endometrium. The underlying mechanisms of action of SERMs in the breast and endometrium that lead to profound differences in the tissue-specific effects of tamoxifen have not yet been elucidated. We have compared the effects of tamoxifen and the pure anti-estrogen ICI 182,780 (Faslodex) in the RUCA-I hormone-responsive rat endometrial cell line in vitro and in vivo. In cell culture, RUCA-I cells responded to both estrogens and anti-estrogens, and the expression of clusterin and complement C3 mRNAs required the presence of estradiol and was repressed in the absence of estradiol or in the presence of the pure anti-estrogen ICI 182,780. Tamoxifen, on the other hand, induced both complement C3 and clusterin mRNA in the absence of estradiol and failed to repress their expression in the presence of estradiol. When grown as subcutaneous xenografts in syngeneic Da/Han rats for 5 weeks, the RUCA-I cells retained their sensitivity to estradiol, as demonstrated by significantly enhanced tumor growth in intact female rats compared with the growth in ovariectomized rats. But neither ICI 182,780 nor tamoxifen had a significant impact on tumor growth in cycling or ovariectomized animals. On the other hand, tamoxifen was potently estrogenic in metastatic lymph nodes, increasing the size of the lymph node tumors almost 6-fold over that seen in the intact cycling animals. In primary tumors, the expression of complement C3 mirrored that seen in vitro, although tamoxifen showed some agonist activity in ovariectomized animals. Tamoxifen also displayed marked agonist activity with respect to clusterin expression and enhanced clusterin mRNA levels and protein in both the primary tumors and lymph metastases in intact and ovariectomized animals. Given the recent demonstration that over-expression of clusterin increases the metastatic potential of breast cancer cells, these data may provide a mechanistic explanation for the increased incidence of endometrial cancer in postmenopausal patients treated with tamoxifen.

Animals↗
PubMed2001

Normal levels of clusterin in cerebrospinal fluid in Alzheimer's disease, and no change after acute ischemic stroke.

The protein clusterin has been suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Its expression is increased in brain regions affected by AD pathology, and to elucidate if there is a concomitant increase of clusterin also in the cerebrospinal fluid (CSF) in different neurological disorders, CSF samples from patients with AD, vascular dementia (VAD), Parkinson's disease (PD), and controls were analysed. Also longitudinal (five occasions) samples from patients with acute stroke were analysed, to follow any degenerative/regenerative phase after acute brain damage. However, there were no changes in CSF-clusterin levels from patients in AD, VAD, PD or acute stroke, as compared to controls. The increase of clusterin in brain tissue is suggested to reflect a regenerative response process, which here is shown not to be followed by a concomitant increase in the CSF. Thus, CSF-clusterin can not be used as an indicator or a diagnostic marker for AD.

Journal Article↗
PubMed1995

Clusterin (apoJ) alters the aggregation of amyloid beta-peptide (A beta 1-42) and forms slowly sedimenting A beta complexes that cause oxidative stress.

Clusterin (apoJ), a multifunctional apolipoprotein made by cells in the brain and many other locations, is associated with aggregated amyloid beta-peptide (A beta) in senile and diffuse plaques of Alzheimer's disease (AD). We observed that purified human serum clusterin partially blocked the aggregation of synthetic A beta 1-42, as shown by centrifugal assays (14,000g x 10 min) and by atomic force (scanning probe) microscopy. Slowly sedimenting A beta complexes were formed in the presence of clusterin, which included aggregates > 200 kDa that resist dissociation by low concentrations of SDS. Clusterin enhanced the oxidative stress caused by A beta, as assayed by oxidative stress in PC12 cells with MTT, which is widely used to estimate neurotoxicity. These indications of enhanced neurotoxicity by the MTT assay were observed in the highly aggregated rapidly sedimenting fraction, but also in more slowly sedimenting "soluble" forms. This novel activity of slowly sedimenting A beta may enhance the neurotoxicity of A beta deposits in AD brains, because soluble complexes have a potential for diffusing to damage distal neurons.

Alzheimer Disease↗
PubMed1993

Human clusterin (CLI) maps to 8p21 in proximity to the lipoprotein lipase (LPL) gene.

Clusterin (gene symbol: CLI) is a post-translationally nicked, two-chain plasma and tissue glycoprotein of 80 kDa. It forms high-density lipoprotein complexes with apolipoprotein A-I in plasma, functions as an inhibitor of the cytolytic reaction of the terminal complement proteins C5 to C9, and is secreted by Sertoli cells in large amounts into the seminal fluid. By isolating and characterizing three partially overlapping cosmid clones, we have established the complete physical map of the clusterin gene which spans about 20 kb. The subchromosomal position of the clusterin gene (CLI) and the order of CLI and the lipoprotein lipase (LPL) gene were determined by fluorescence in situ hybridization. We show that CLI, previously assigned to chromosome 8, is located on 8p21 proximal to the LPL locus. Based on this localization we consider clusterin as a novel candidate gene determining susceptibility to atherosclerosis.

Arteriosclerosis↗
PubMed1993

Abnormal distribution of retinal clusterin in retinitis pigmentosa.

Increased expression of clusterin mRNA is associated with neurodegenerative states, including retinas affected by retinitis pigmentosa (RP). We have investigated the distribution of immunoreactive clusterin in normal and RP-affected retinas. Reactivity at the inner limiting membrane, plexiform layers, and photoreceptors in normal retina accords well with clusterin's postulated role as a membrane protective agent. In RP-affected retina the organized distribution is lost and overall reactivity appears decreased. The changes in this case may reflect increased turnover or removal of clusterin, perhaps via interaction with components of the immune system.

Adult↗
PubMed1993

Comparison of clusterin gene expression in normal and dystrophic human retinas.

To gain insight into the mechanisms underlying altered clusterin expression in retinal degeneration, the cellular distribution of clusterin mRNA in normal and in retinitis pigmentosa-affected retinas was compared using in situ hybridization. In contrast to the normal retina, where clusterin mRNA is localized in the inner nuclear and ganglion cell layers, a clustered distribution is observed throughout the dystrophic retina. The results indicate an expression of clusterin gene in normal retinal neurons and suggest that its altered regulation in neurodegeneration is not purely a glial cell phenomenon.

Adult↗
PubMed2005

Ketogenic diet prevents clusterin accumulation induced by kainic acid in the hippocampus of male ICR mice.

We investigated the effect of ketogenic diet (KD) on clusterin accumulation in the kainic acid (KA)-induced seizure model. Two days after KA administration, strong clusterin-like immunoreactivity (IR) was detected in the hippocampus in the normal diet (ND)-fed mice. But in the KD-fed mice, few clusterin-like IR was detected. These results indicate that KD has neuroprotective effects throughout diminishing nuclear clusterin accumulation that is involved in caspase-3 independent cell death mechanism.

Animal Nutritional Physiological Phenomena↗
PubMed1999

Clusterin (SGP-2) gene expression is cell cycle dependent in normal human dermal fibroblasts.

In confluent human dermal fibroblasts brought to quiescence (G0) by serum starvation, the S phase peaked at 24 h after serum re-addiction and G2/M phase peaked at 36 h. This was confirmed by titration of h-gas1 mRNA (a marker of G0 phase) and histone H3 (a marker of S phase). Clusterin mRNA accumulation progressively increased in cells proceeding to confluence after seeding and to quiescence upon serum starvation, and peaked at around G0, in parallel with h-gas1 mRNA. At 6 h (roughly G1 phase) clusterin transcript formed a second peak, followed by a gradual decrease until 36 h. Correspondence of clusterin protein accumulation to its mRNA occurred solely with regard to the G0 peak but not to the second one. The possible meaning of the cell cycle related clusterin gene expression is discussed.

Blotting, Northern↗
PubMed2004

ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo.

Apolipoprotein E (apoE) and clusterin can influence structure, toxicity, and accumulation of the amyloid-beta (Abeta) peptide in brain. Both molecules may also be involved in Abeta metabolism prior to its deposition. To assess this possibility, we compared PDAPP transgenic mice that develop age-dependent Abeta accumulation in the absence of apoE or clusterin as well as in the absence of both proteins. apoE(-/-) and clusterin(-/-) mice accumulated similar Abeta levels but much less fibrillar Abeta. In contrast, apoE(-/-)/clusterin(-/-) mice had both earlier onset and markedly increased Abeta and amyloid deposition. Both apoE(-/-) and apoE(-/-)/clusterin(-/-) mice had elevated CSF and brain interstitial fluid Abeta, as well as significant differences in the elimination half-life of interstitial fluid Abeta measured by in vivo microdialysis. These findings demonstrate additive effects of apoE and clusterin on influencing Abeta deposition and that apoE plays an important role in regulating extracellular CNS Abeta metabolism independent of Abeta synthesis.

Amyloid beta-Peptides↗
PubMed1996

Effects of intermittent androgen suppression on the stem cell composition and the expression of the TRPM-2 (clusterin) gene in the Shionogi carcinoma.

The proportion of tumorigenic stem cells and the expression of the apoptosis-related gene, TRPM-2 (clusterin), were studied in populations of Shionogi carcinoma cells subjected to multiple cycles of androgen withdrawal and replacement (intermittent androgen suppression). The parent androgen-dependent cell line was initially transplanted into a male mouse which was castrated when the estimated weight of the resultant tumour became approximately 3 g. After the tumour had regressed to 40% or less of the original weight, it was transplanted into the next non-castrated male. This was repeated for four cycles of transplantation and castration-induced apoptosis before the tumour progressed to an androgen-independent state. The proportion of total stem cells in the tumour, as determined by in vivo limiting dilution assays in male mice, was constant during the first three cycles but increased 15-fold between the third and fourth cycles. In the parent androgen-dependent tumour before androgen ablation, the androgen-independent stem cell population formed 0.8% of the total stem cell compartment. After the fourth cycle this population increased to 47%; a population of similar size (33%, P = 0.8) was found in the androgen-independent recurrent form of the tumour induced by one-time castration. Whether androgen withdrawal therapy was intermittent or continuous, conversion to androgen independence thus occurred when one-third to one-half of the total stem cell compartment was populated by androgen-independent stem cells. The androgen-repressed TRPM-2 (clusterin) gene was actively expressed in regressing tumours after androgen ablation, and also became constitutively expressed in non-regressing tumours after the first and subsequent cycles of androgen withdrawal. Staining of cytoplasm and nuclei with anti-clusterin antibody was observed in androgen-dependent tumour cells after each cycle of intermittent androgen suppression; the nuclear staining was more intense in recurrent androgen-independent cells. The anomalous nuclear localization of clusterin, an anti-cytolytic TRPM-2 encoded protein, may serve to inhibit early events in the apoptotic process and thereby foster the generation and outgrowth of androgen-independent stem cells in an androgen-depleted environment.

Androgens↗
PubMed2002

Clusterin.

Clusterin is an enigmatic glycoprotein with a nearly ubiquitous tissue distribution and an apparent involvement in biological processes ranging from mammary gland involution to neurodegeneration in Alzheimer's disease. Its major form, a 75-80 kDa heterodimer, is secreted and present in physiological fluids, but truncated forms targeted to the nucleus have also been identified. Upregulation of clusterin mRNA and protein levels detected in diverse disease states and in in vitro systems have led to suggestions that it functions in membrane lipid recycling, in apoptotic cell death, and as a stress-induced secreted chaperone protein, amongst others. Recent studies of knockout mice have further complicated the picture by implicating clusterin in exacerbating neuronal death in hypoxia-ischemia. The question of whether clusterin is a multifunctional protein, or deploys a single primary function influenced by cellular context, remains a central issue continuing to stimulate interest in this unusual molecule.

Animals↗
PubMed1999

Clusterin in bovine spongiform encephalopathy (BSE).

Clusterin mRNA, detected in increased quantities in the cervical spinal cord of cattle with bovine spongiform encephalopathy (BSE), was localized mainly in the neuroglia (including astrocytes) of the lateral and ventral areas of white matter. Axonal degeneration was also observed in these areas. The dorsal horns of the spinal cord in which BSE prion protein (PrP(BSE)) was deposited did not exhibit strong clusterin "up-regulation" but showed increased clusterin immunolabelling with a punctate distribution in the neuropil. Labelling of adjacent sections of the grey matter in BSE-affected spinal cord and thalamus demonstrated that the clusterin was deposited in association with extracellular PrP(BSE).

Animals↗