Disease relevance of Clu

• Expression of clusterin in Müller cells of the rat retina after pressure-induced ischemia [1].
• In human myocardial infarcts, clusterin was found on scattered, morphologically viable cardiomyocytes within the infarcted area that were negative for complement [2].
• Clusterin protects cells by inhibiting complement and colocalizes with complement on jeopardized human cardiomyocytes after infarction [2].
• Furthermore, clusterin may also help to differentiate between tubular and glomerular forms of proteinuria [3].
• Clusterin is a sulfated glycoprotein produced by neurons and by resting and activated astrocytes that has several putative functions, including protective responses to brain injury [4].

Psychiatry related information on Clu

• The abundance of sulfated glycoprotein 2 RNA is increased in hippocampus from patients with Alzheimer disease and Pick disease, whereas transferrin RNA is not strongly modulated in these conditions [5].
• At 29 degrees C, there were no significant differences in REM sleep or in Tb between CLI and SAL rats [6].
• This inhibition may result in reduced availability of the second messengers IP3 and DAG that are derivates of the PIP cycle, and this action is currently a leading hypothesis regarding lithium's therapeutic and prophylactic effect in affective disorders [7].

High impact information on Clu

• Likewise, none of the PCNA or vimentin-positive cells expressed clusterin at detectable levels [8].
• 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 [8].
• Molecular cloning of the human complement inhibitor SP-40,40, has revealed strong homology to a major rat and ram Sertoli cell product, sulfated glycoprotein-2, known also as clusterin [9].
• DNA sequence analysis has shown that these two recombinants represent the genes for sulfated glycoprotein 2 and transferrin [5].
• Although the function(s) of the products encoded by the TRPM-2 gene remains unclear, their presence provides a remarkable and early indicator of programmed cell death in many types of mammalian cells [10].

Chemical compound and disease context of Clu

• However, we have found high levels of SGP-2 expression in the epithelial component of carcinomas of the prostate and seminal vesicle after initiation with N-nitroso-N-methylurea and promotion with testosterone propionate [11].
• We have investigated the regulation of clusterin expression by estradiol and anti-estrogens in RUCA-I rat endometrial adenocarcinoma cells in vitro and in vivo [12].
• We have examined the expression of the multifunctional protein clusterin in the axotomized red nucleus, at the lesion site in the lateral funiculus of C3, as well as along the Wallerian degeneration in the lateral funiculus of T1 [13].
• Clusterin expression may increase either due to blockade of tonic angiotensin-mediated inhibition, or as an adaptive response to renal ischemia [14].
• Previous work from this and other laboratories has established that clusterin, Clq and C4 messenger RNAs are elevated during Alzheimer's disease, and in response to deafferenting and excitotoxic brain lesion [15].

Biological context of Clu

• Genomic organization and expression of the rat TRPM-2 (clusterin) gene, a gene implicated in apoptosis [16].
• METHODS: We isolated ductal tissue from rat pancreas and cultured it to develop epithelial cell explants for transfection of the Clu cDNA as well as for treatment of clusterin protein [17].
• This activity might reconcile the opposite purported influences of clusterin on cell survival and explain how clusterin can be causally involved in neurodegeneration [18].
• Insulin cell differentiation was also increased in a dose-dependent manner by treating duct cells in culture with clusterin, indicating a growth-factor-like action of clusterin in insulin cell differentiation [17].
• Immunocytochemistry using antisera against clusterin or glutamine synthase combined with the TUNEL method or immunocytochemistry using antisera activated caspase 3 and electron microscopy revealed that some clusterin-labeled Müller cells underwent apoptotic cell death [1].

Anatomical context of Clu

• Finally, we demonstrate that ectopic expression of clusterin in PC12 cells elongates neurite-formation triggered by NGF and induces spontaneous neurite outgrowth even in the absence of NGF [19].
• Both clusterin and SCLIP are co-localized at the perinuclear region and growth cone of PC12 cells [19].
• Primer extension, S1 nuclease protection, and extensive polymerase chain reaction analysis suggest that the TRPM-2 transcript from the prostate and the SGP-2 transcript from the testis are in fact identical and only contain the exon I sequence identified in the TRPM-2 genomic clone [16].
• AIMS/HYPOTHESIS: We recently reported that expression of the gene encoding clusterin (Clu) is upregulated in the regenerating pancreas, particularly in tissues undergoing differentiation [17].
• This led us to propose that clusterin participates in the cytodifferentiation of pancreatic tissue, particularly the endocrine islet cells [17].

Associations of Clu with chemical compounds

• In addition, we show that the minimal domains for the interaction are mapped to the C-terminal valine-rich region (367-447) of clusterin and the N-terminal palmitoylation and membrane attachment site (1-34) of SCLIP [19].
• The induction of clusterin mRNA was blocked by actinomycin D which indicates that TSA regulates clusterin expression at the transcriptional level [20].
• Hydrogen peroxide and ADP-ribose induce TRPM2-mediated calcium influx and cation currents in microglia [21].
• Proteasomal stress (MG-132 and PI-1 treatments) and apoptotic stress (okadaic acid treatment) did not affect clusterin expression which indicates that the induction of clusterin expression requires more specific inducers than cellular stress in general [20].
• Clusterin bound to single annexin V-positive or annexin V and propidium iodide-positive H9c2 cells [2].
• We demonstrated that 50% of the cells overexpressing clusterin escaped from TNFalpha- and actinomycin D-induced cell death [22].

Physical interactions of Clu

• Taken together, these results suggest that the clusterin interacts with SCLIP and the interaction may act as an important modulator during neuronal differentiation [19].

Regulatory relationships of Clu

• Nerve growth factor and epidermal growth factor stimulate clusterin gene expression in PC12 cells [23].
• TGF-beta 1 synthesis or fibroblast proliferation but prevented the differentiation of fibroblasts into myofibroblasts and blocked clusterin expression [24].
• In conclusion, a marked, yet reversible induction of clusterin occurred in chemically induced polycystic kidney disease [25].
• Densitometry scans of Northern blots indicated that vinclozolin, p,p'-DDE, and flutamide each induced TRPM-2 mRNA and repressed C3 mRNA compared to vehicle-treated T-implanted controls [26].

Other interactions of Clu

• Furthermore, in 8-wk-old rats that were fed a high-sucrose diet, the DAG oil group accumulated less visceral fat and showed decreases of plasma adiponectin and suppressed increases of plasma insulin, leptin, and the size of islet of Langerhans compared with the TAG oil group [27].
• Using the bioassay developed for the ovine protein, rat clusterin was purified to apparent homogeneity by HPLC from primary Sertoli cell-enriched culture media [28].
• Using an affinity-purified rabbit antiserum raised against recombinant clusterin, we established an enzyme-linked immunosorbent assay to measure the urinary excretion of clusterin after bilateral renal ischemia, in the (cy/ +) rat model of autosomal-dominant polycystic kidney disease and in the FHH rat model of focal segmental glomerulosclerosis [3].
• Testicular transferrin mRNA levels from irradiated rats decreased in comparison to levels in the normal rat, whereas SGP-2 mRNA levels were unchanged [29].
• To localize NGF- and EGF-responsive elements we isolated the clusterin promoter and tested it in PC12 cell transfections [23].

Analytical, diagnostic and therapeutic context of Clu

• Northern blots show a wide tissue distribution for the 2.0-kb SGP-2 message, and computer sequence analysis indicates a significant relationship between SGP-2 and human apolipoprotein A-I [30].
• Biosynthesis and molecular cloning of sulfated glycoprotein 2 secreted by rat Sertoli cells [30].
• Quantitative evaluation by immunoblotting confirmed that clusterin expression continuously increased and showed a peak value at 3 days after ischemic injury (to 1300% of control levels), and then decreased again to 400% of controls at 4 weeks postlesion [1].
• In situ hybridizations from mouse brain showed a distribution of TRPM2, which is compatible with the expression in microglial cells [21].
• Regression of the rat ventral prostate gland following castration is accompanied by the induced expression of messenger RNA encoding Testosterone Repressed Prostate Message-2 (TRPM-2) [31].

References