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PubMed2004

Transcriptional down-regulation of the platelet ADP receptor P2Y(12) and clusterin in patients with systemic lupus erythematosus.

Cardiovascular complications are common in systemic lupus erythematosus (SLE) and myocardial infarctions are the leading cause of increased mortality. The ADP receptor P2Y(12) plays a central role in platelet activation and the P2Y(12) blocker clopidogrel reduces the incidence of cardiovascular events. Clusterin, a complement inhibitory protein suggested to be involved in the pathogenesis of SLE, has been found recently in a microarray study to be expressed at very high levels in platelets. Using a new protocol for mRNA quantification in platelets we set out to study if gene expression is altered in SLE patients compared with a healthy control group. Quantitative assay based on real-time PCR was used to measure mRNA expression, Western blot for P2 receptor protein expression and PFA-100 for platelet aggregation. The P2Y(12) receptor expression was decreased in SLE compared to the controls (P < 0.05), while expression of P2Y(1) and P2X(1) were unaltered. These findings were consistent at the protein level. The clusterin mRNA expression was very high. However, SLE patients had significantly lower levels than controls (P < 0.05). Platelet aggregation was similar in both groups. It may be suggested that a decreased level of P2Y(12) receptors could represent a protective response in SLE against thrombotic complications. Lowered clusterin levels could be involved in the pathogenesis of SLE due to decreased protective effects. These findings could help to achieve a better understanding of the platelet function in SLE and serve as a guide for further research and drug use.

Adolescent↗
PubMed1995

Regulation of renal growth factors and clusterin by AT1 receptors during neonatal ureteral obstruction.

Unilateral ureteral obstruction (UUO) in the neonate impairs growth of the ipsilateral kidney. Since renal renin expression is increased by UUO, we hypothesized that, by activation of AT1 receptors, angiotensin II (ANG II) regulates expression of transforming growth factor-beta 1 (TGF-beta 1) and epidermal growth factor (EGF) in the obstructed kidney. Sprague-Dawley rats underwent left UUO or sham operation within the first 48 h of life and received losartan, 40 mg.kg-1.day-1, or saline. After 14 days, steady-state renal mRNA was determined for renin, TGF-beta 1, EGF, and clusterin. Losartan reduced the DNA content of the intact kidneys but did not further decrease that of the obstructed kidney. Losartan increased renal renin expression and decreased EGF expression by 80%, regardless of UUO. In contrast, losartan reduced TGF-beta 1 expression by 34% in obstructed kidneys but did not affect TGF-beta 1 in intact kidneys. Losartan increased clusterin expression by 60% in obstructed kidneys and seven-fold in intact kidneys. We conclude that activation of the ANG II AT1 receptor is necessary for normal renal growth and that TGF-beta 1 is regulated by AT1 receptors in the obstructed, but not intact, kidneys. Through AT1 receptors, endogenous ANG II stimulates EGF and inhibits clusterin expression.

Angiotensin II↗
PubMed1994

Localization of proliferating cell nuclear antigen, vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for a heterogenous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells.

The mechanisms leading to the recovery of the kidney after ischemic acute renal failure are poorly understood. To explore the role played by mitogenesis and dedifferentiation in this repair process and to identify whether the genetic response of the nephron segments reflects the level of susceptibility to injury, the temporal and nephron segment expressions of various proteins implicated in mitogenesis, differentiation, and injury were determined. Proliferating cell nuclear antigen (PCNA), a marker for the G1-S transition in the cell cycle and hence mitogenesis, was detected primarily in the S3 segment of the proximal tubule, with maximal expression at 2 d postischemia. Vimentin, normally present in mesenchymal cells but not epithelial cells, and hence a marker for the state of differentiation, was prominently expressed in the S3 segment 2-5 d postischemia. In the S3 segments in the outer stripe of the medulla cells that stained positively for PCNA also stained positively for vimentin. Clusterin, a marker for cell injury, was expressed primarily in the S3 segment and in the distal tubule with distinct staining patterns in each segment. None of the cells that stained with clusterin antibodies were positively stained with PCNA or vimentin antibodies. Likewise, none of the PCNA or vimentin-positive cells expressed clusterin at detectable levels. Thus, in the S3 segment, where there is significant ischemic injury, surviving cells express markers indicating that they undergo mitogenesis and dedifferentiate in the postischemic period. While there is some expression of c-Fos in the S3 segment, c-Fos was expressed predominantly, at 1 and 3 h postischemia, in the nuclei of the distal nephron, particularly in the thick ascending limb. The data support the view that the mature renal S3 segment epithelial cell can be a progenitor cell.

Animals↗
PubMed2005

Knock-down of the cytoprotective gene, clusterin, to enhance hormone and chemosensitivity in prostate and other cancers.

Discovery and targeting of genes mediating treatment resistance may lead to development of novel therapies that delay progression of recurrent and refractory cancers. Clusterin is a stress-associated cytoprotective chaperone expressed in many cancers that is upregulated in an adaptive cell survival manner by various apoptotic triggers and confers treatment resistance. Here, we review clusterin's functional role in regulating treatment-induced apoptosis and the use of a second generation antisense oligonucleotide to inhibit clusterin expression to enhance the cytotoxic effects of hormone- and chemotherapy in prostate and other xenograft models, as well as in recent human trials.

Animals↗
PubMed2006

Clusterin is a secreted marker for a hypoxia-inducible factor-independent function of the von Hippel-Lindau tumor suppressor protein.

Germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene predispose people to renal cancer, hemangioblastomas, and pheochromocytomas in an allele-specific manner. The best documented function of the VHL gene product (pVHL) relates to its ability to polyubiquitinate, and hence target for destruction, the alpha subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF). pVHL mutants linked to familial pheochromocyctoma (type 2C VHL disease), in contrast to classical VHL disease, appear to be normal with respect to HIF regulation. Using a simple method for identifying proteins that are differentially secreted by isogenic cell line pairs, we confirmed that the HIF targets IGBP3 and PAI-1 are overproduced by pVHL-defective renal carcinoma cells. In addition, cells lacking wild-type pVHL, including cells producing type 2C pVHL mutants, were defective with respect to expression and secretion of clusterin, which does not behave like a HIF target. Decreased clusterin secretion by pVHL-defective tumors was confirmed in vivo by immunohistochemistry. Therefore, clusterin is a secreted marker for a HIF-independent pVHL function that might be especially important in pheochromocytoma development.

Adrenal Gland Neoplasms↗
PubMed2003

Loss of clusterin both in serum and tissue correlates with the tumorigenesis of esophageal squamous cell carcinoma via proteomics approaches.

AIM: To identify the differentially secreted proteins or polypeptides associated with tumorigenesis of esophageal squamous cell carcinoma (ESCC) from serum and to find potential tumor secreted biomarkers. METHODS: Proteins from human ESCC tissue and its matched adjacent normal tissue; pre-surgery and post-surgery serum; and pre-surgery and normal control serum were separated by two-dimensional electrophoresis (2-DE) to identify differentially expressed proteins. The silver-stained 2-DE were scanned with digital ImageScanner and analyzed with ImageMaster 2D Elite 3.10 software. A cluster of protein spots differentially expressed were selected and identified with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). One of the differentially expressed proteins, clusterin, was down-regulated in cancer tissue and pre-surgery serum, but it was reversed in post-surgery serum. The results were confirmed by semi-quantitative reverse-transcription (RT)-PCR and western blot. RESULTS: Comparisons of the protein spots identified on the 2-DE maps from human matched sera showed that some proteins were differentially expressed, with most of them showing no differences in composition, shape or density. Being analyzed by MALDI-TOF-MS and database searching, clusterin was differentially expressed and down-regulated in both cancer tissue and pre-surgery serum compared with their counterparts. The results were also validated by RT-PCR and western blot. CONCLUSION: The differentially expressed clusterin may play a key role during tumorigenesis of ESCC. The 2DE-MS based proteomic approach is one of the powerful tools for discovery of secreted markers from peripheral.

Aged↗
PubMed2000

Tumor progression is accompanied by significant changes in the levels of expression of polyamine metabolism regulatory genes and clusterin (sulfated glycoprotein 2) in human prostate cancer specimens.

Using Northern blotting, the expression levels of the genes for polyamine metabolism regulatory proteins and clusterin have been measured in a series of 23 human prostate cancers (CaPs) dissected from radical prostatectomy specimens. Patient matched, nontumor tissue was dissected from benign areas of the gland. The results indicate that transcripts encoding ornithine decarboxylase (ODC), ODC antizyme, adenosylmethionine decarboxylase, and spermidine/spermine N1-acetyltransferase (SSAT) were significantly higher, whereas clusterin (sulfated glycoprotein 2) mRNA was significantly lower in tumors compared with the benign tissue. All mRNA levels were compared with those of histone H3 and growth arrest-specific gene 1, markers of cell proliferation and cell quiescence, respectively, and glyceraldehyde 3-phosphate dehydrogenase, a housekeeping gene. In poorly differentiated and locally invasive CaPs and in tumors with unfavorable prognosis or total prostate-specific antigen (PSA) levels > 10.0 ng/ml at diagnosis, an overall increase in the levels of H3 mRNA and a decrease in growth arrest-specific gene 1 mRNA was detected, indicative of higher proliferation activity, whereas the differences in expression levels for the polyamine metabolism and clusterin genes were higher. ODC and SSAT changes were positively correlated in normal tissue but not in high-grade cancer, whereas ODC antizyme and SSAT changes were positively correlated in more malignant CaPs but not in normal tissue. Tumor classification based on the changes in expression levels of all of the genes studied could be correlated to differentiation grade and local invasiveness classification systems in 72.2 and 83.3% of the cases, respectively. In a 1-year follow-up period, three patients whose CaPs ranked as less aggressive according to clinical staging, but classified as advanced cancers with the proposed molecular classification, showed increases in total PSA levels, indicative of tumor relapse. Thus, molecular classification, based on gene expression, may enhance the available prognostic tools for prostate tumors.

Acetyltransferases↗
PubMedDate not supplied

Correlation between clusterin-positive spermatozoa determined by flow cytometry in bull semen and fertility.

The objectives were to 1) develop a rapid and accurate method for detection of clusterin-positive spermatozoa (CPS) in bull semen and 2) determine the utility of incidence of CPS for prediction of fertility of bull semen in comparison to routine semen quality traits. Semen from 3 bulls was immunostained with anti-bovine clusterin antibody and with FITC-conjugated anti-rabbit IgG for method development. Clusterin-positive spermatozoa were determined by flow cytometry (FCM) and fluorescence microscopy, and results were compared by paired t test. There was no difference between FCM and microscopic techniques (P = .81). Flow cytometry was then used for determination of CPS in semen of 48 bulls with known fertility. Significant inverse relationships were found between the percentage of CPS and raw nonreturn rate (r = -.30), adjusted nonreturn rate (r = -.58), and estimated relative conception rate (ERCR; r = -.60). Estimated relative conception rate is potentially a very accurate method for determining fertility, and it resulted in highest correlation with CPS. An inverse relationship was observed between the percentage of CPS and prefreeze and postfreeze motility (r = -.51), whereas a direct relationship was found between CPS and primary, secondary, tertiary, and total sperm abnormalities (r = .52, .77, .32, and .58, respectively). The fractions of motile and abnormal spermatozoa, with the exception of tertiary abnormalities, were inversely correlated with 2 or more of the fertility estimates, but none of them showed the characteristic increase in correlation with improvement of accuracy of fertility estimate as demonstrated by CPS. We conclude that FCM is useful for objective and efficient detection of CPS in bull semen. The results suggest that the percentage of CPS in bull semen is potentially a better predictor of fertility than sperm motility or abnormal morphology.

Animals↗
PubMed2005

Clusterin and Alzheimer's disease.

Clusterin (apolipoprotein J) is a ubiquitous multifunctional glycoprotein with the capability to interact with a broad spectrum of molecules, among them the Alzheimer's Abeta peptide. Due to its co-localization with fibrillar deposits in systemic and cerebral amyloid disorders, clusterin is also considered an amyloid-associated protein. Although no genuine function has been attributed to this protein so far, it has been implicated in a wide variety of physiological and pathological processes, a role that may vary according to the protein maturation, sub-cellular localization, and the presence of certain tissue- or cell-specific factors. This review focuses on the importance of clusterin in health and disease conditions, with particular emphasis in its role in Abeta amyloidosis and other disorders of protein folding.

Alzheimer Disease↗
PubMed1995

The expression of the avian clusterin gene can be driven by two alternative promoters with distinct regulatory elements.

Clusterin cDNA has been isolated as a copy of a mRNA overexpressed in a wide variety of biological disorders, including tissue regression, brain injuries and oncogenic cell transformation. While the molecular cloning of the rat and the human clusterin genes has revealed a high degree of conservation of the genomic organization between mammals, the avian locus described here illustrates several divergent features. The avian gene has the particularity to be transcribed from at least two different promoters, both of which are active in transient expression assays using the quail QT6 transformed cell line. The detection of the two clusterin mRNA species by reverse-transcription-mediated PCR reveals a coordinated initiation of transcription from both promoters in all organs tested. In possible relation to the bipartite organization of the avian regulatory region, the putative cis-elements described in the unique mammalian promoters appear divided among the two avian promoters. In addition, the sequence comparison of avian and mammalian regulatory sequences has allowed the identification of a conserved putative cis-element which appears to be the target for specific DNA-binding factors.

Amino Acid Sequence↗
PubMed1994

Clusterin as a marker for ischaemic Purkinje cells in human brain.

Clusterin has been implicated in cell death both in peripheral tissues and in the central nervous system. In the present study, expression of clusterin in the cerebellar cortex was examined in two cases with hypoxic brain damage and in one case with cerebellar infarction. Intense staining of Purkinje cells was observed in each case, and these cells showed the shrunken and pyknotic appearance characteristic of irreversible ischaemic damage. In the cerebella of neurologically normal control cases, as well as in those of some other neurodegenerative diseases, no staining or only punctate staining of Purkinje cells was observed. The results provide additional evidence supporting an association of clusterin with dying neurons in human brain.

Adult↗
PubMed1997

The glycoproteins that occur in the colloids of senescent porcine pituitary glands are clusterin and glycosylated albumin fragments.

Periodic acid-Schiff-positive colloids occur in the pituitary glands of many vertebrates. These colloids are surrounded by folliculo-stellate (FS) cells and increase dramatically in number and size with age. The characterization of these colloidal substances is necessary for the establishment of FS cell function. In a previous study we showed that these colloids in the senescent pituitary contain a number of glycoproteins; however, the characterization of these glycoproteins has not yet been carried out. To characterize the pituitary colloid, we purified the colloids by centrifugation and Percoll gradient. The isolated colloids were unable to be solubilized in a regular buffer since they were very dense. However, solubilization was accomplished in sodium dodecyl sulfate (SDS) lysis buffer following treatment with exoglycosidase. Analysis using SDS-polyacrylamide gel electrophoresis showed that the porcine pituitary colloids contain four proteins, CP26, CP40, CP48 and CP60, whose estimated molecular weights were 26 kD, 36-43 kD, 48 kD, and 60 kD, respectively. Staining with concanavalin A (ConA) showed that both CP26 and CP40 were glycoproteins. Moreover, N-terminal amino acid sequencing and Western blot analysis revealed CP26, CP48 and CP60 to be porcine albumin while CP40, the major protein in the colloids, proved to be clusterin. Therefore we report here that the glycoproteins that occur in senescent porcine pituitary colloids are of two types, namely, albumin fragments and clusterin.

Aging↗
PubMed2006

Clusterin and DNA repair: a new function in cancer for a key player in apoptosis and cell cycle control.

The glycoprotein clusterin (CLU), has two known isoforms generated in human cells. A nuclear form of CLU protein (nCLU) is pro-apoptotic, while a secretory form (sCLU) is pro-survival. Both forms are implicated in various cell functions, including DNA repair, cell cycle regulation, and apoptotic cell death. CLU expression has been associated with tumorigenesis and the progression of various malignancies. In response to DNA damage, cell survival can be enhanced by activation of DNA repair mechanisms, while simultaneously stimulating energy-expensive cell cycle checkpoints that delay the cell cycle progression to allow more time for DNA repair. This review summarizes our current understanding of the role of clusterin in DNA repair, apoptosis, and cell cycle control and the relevance.

Apoptosis↗
PubMed1992

Analysis of differentially expressed genes in retinitis pigmentosa retinas. Altered expression of clusterin mRNA.

The molecular and cellular processes underlying photoreceptor degeneration in retinitis pigmentosa (RP) are unknown. We have investigated gene expression in diseased retinas using differential hybridization screening of a retinal cDNA library with probes derived from normal and RP retinal RNA. Most differential clones detected corresponded to transcripts absent from the dystrophic state, including e.g. opsin. However, one clone was noticeably increased in RP in comparison with the control: partial sequencing showed it encoded clusterin. Increased expression of clusterin has been identified in several cases of tissues undergoing apoptosis (programmed cell death), and our finding suggests that the degenerative changes in advanced RP may represent another example of apoptosis, possibly with common causative mechanisms.

Adult↗
PubMed1994

Transforming growth factor-beta 1 induces neuronal and astrocyte genes: tubulin alpha 1, glial fibrillary acidic protein and clusterin.

Transforming growth factor-beta 1 was studied as a possible regulator of messenger RNAs in astrocytes and neurons that increase after hippocampal deafferentation by perforant path transection: tubulin alpha 1, clusterin and glial fibrillary acidic protein messenger RNA. Because transforming growth factor-beta 1 messenger RNA is increased after this lesion, we examined which messenger RNA lesion responses could be induced by transforming growth factor-beta 1 alone. Porcine transforming growth factor-beta 1 infused into the lateral ventricle elevated the messenger RNAs for tubulin alpha 1, clusterin and glial fibrillary acidic protein 24 h after infusion in the ipsilateral hippocampus. As assayed by nuclear run-on, the transcription of glial fibrillary acidic protein RNA was increased in the ipsilateral hippocampus after perforant path transection and in primary rat astrocyte cultures by transforming growth factor-beta 1. In contrast, transforming growth factor-beta 1 did not change apolipoprotein-E messenger RNA or transcription, or growth associated protein-43 messenger RNA levels. We conclude that transforming growth factor-beta 1 increases subsets of neuronal and astrocyte messenger RNAs coding for cytoskeletal proteins that are also elevated in response to experimental lesions and Alzheimer's disease. This suggests that transforming growth factor-beta 1 might be a local organizing factor of neuronal and astrocyte responses to brain injury.

Animals↗
PubMed1995

Complement and clusterin in the spinal cord dorsal horn and gracile nucleus following sciatic nerve injury in the adult rat.

We provide evidence for activation of the complement cascade in the dorsal horn of the spinal cord and in the gracile nucleus in the brainstem following sciatic nerve transection in the adult rat. Immunocytochemical analyses showed immunoreactivity for endogenous immunoglobulin G as shown by immunostaining with F(ab')2 antibodies, as well as complement factors C1, C1q, C3, C3d and C9 in the appropriate central termination areas of the injured sciatic nerve. Results from double labelling immunocytochemistry showed a strong association between immunoglobulin and complement factors on the one hand and reactive microglia on the other. However, some complement immunoreactivity was also found in the neuropil, possibly representing secreted complement. In situ hybridization with an oligonucleotide probe showed a marked increase in C3 messenger RNA, indicating local synthesis of C3 protein. In parallel with activation of complement, there was an increased immunoreactivity for the putative complement inhibitor clusterin, which co-localized with glial fibrillary acidic protein-positive astrocytes. In situ hybridization showed an increased labelling of clusterin messenger RNA. These findings indicate that complement activation and up-regulation of complement inhibitors are prominent central responses to peripheral sensory nerve injury. These responses may therefore be important elements underlying so-called transganglionic degenerative changes in primary sensory axons and terminals.

Animals↗
PubMed1991

The gene for SP-40,40, human homolog of rat sulfated glycoprotein 2, rat clusterin, and rat testosterone-repressed prostate message 2, maps to chromosome 8.

Sulfated glycoprotein 2 (SGP-2) is a rat glycoprotein that is particularly abundant in seminal fluid, where it is found associated with the acrosome and the tail of mature spermatozoa; for this reason it has been suggested that it has an important role in spermatogenesis. On the basis of nucleotide sequence homology, it has been proposed that the orthologous human gene is that coding for serum protein-40,40 (SP-40,40), a serum protein also called complement lysis inhibitor (CLI), SP-40,40 has been shown to act as a control mechanism of the complement cascade: in fact, it prevents the binding of a C5b-C7 complex to the membrane of the target cell and in this way inhibits complement-mediated cytolysis. SGP-2 and SP-40,40 seem then to be part of different biological systems. Furthermore it has been shown that another protein, testosterone-repressed prostate message 2 (TRPM-2), shares sequence homology with SGP-2 and SP-40,40. TRPM-2 is expressed at high levels and in a temporally precisely defined manner in dying cells, an observation that would suggest its involvement in the cascade of events leading to cell death. We have used a large panel of 24 mouse/human hybrid cell lines and a cDNA for SGP-2, which is also highly homologous to that for rat clusterin, to map the chromosomal location of the orthologous human gene. The mapping data and the Southern analysis presented in this paper, in addition to the data available from the literature, strongly suggest that in the human genome there is a single locus homologous to the probe used and that it codes for the protein which has been called, in different species, SP-40,40, SGP-2, clusterin, and TRPM-2. The chromosomal mapping of the locus for this multiname protein should facilitate its cloning and a better understanding of the apparently many biological functions of its product.

Animals↗
PubMed2004

Increased clusterin expression in old but not young adult S100B transgenic mice: evidence of neuropathological aging in a model of Down Syndrome.

S100B is a calcium-binding protein, localized to astroglial cells, which has a variety of neurotrophic functions, including roles in serotonergic neuronal growth, synaptogenesis dendritic branching and apoptosis. In humans, the gene for S100B is found on chromosome 21, within what is considered the obligate region for Down Syndrome (DS) and levels of S100B are increased in brain of both DS and Alzheimer's Disease (AD). We have been characterizing a transgenic mouse overexpressing this protein and have previously found evidence of pathological changes in brains of the mice. In the current study, we have examined the expression of clusterin, a protein expressed in aging neurons, in the mice at two ages. Our findings show increased clusterin expression in the aged S100B mice compared to their CD-1 controls, a finding we have interpreted as further evidence of pathological brain aging.

Aging↗