Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As high grade PIN is commonly associated with concomitant cancer, current literature recommends re-biopsy of patients with high grade PIN. This paper describes the prevalence of high grade prostatic intra-epithelial neoplasia (PIN) from three independent clinical settings, reported by a single pathologist (MCP). High grade PIN was diagnosed in biopsies from 131 of the 1205 (11%) of patients in whom cancer was suspected in hospital practice, 42 of the 202 (20%) asymptomatic men screened for prostate cancer and 29 of the 118 (25%) patients presenting with prostatism in a case finding study. Re-biopsy on this scale has major clinical and cost implications. However, from a literature review, there is evidence to suggest that the risk of concomitant cancer with high grade PIN may be stratified according to serum PSA. This opinion should be tested prospectively.
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PMID:Prevalence of prostatic intra-epithelial neoplasia (PIN) in biopsies from hospital practice and pilot screening: clinical implications. 1249 20

p62 is a multifunctional cytoplasmic protein able to noncovalently bind ubiquitin and several signaling proteins, suggesting a regulatory role connected to the ubiquitin-proteasome pathway. No studies to date have linked p62 protein expression with pathological states. Here we demonstrate the overabundance of p62 protein in malignant breast tissue relative to normal breast tissue. The proteasome inhibitor PSI increased p62 mRNA and protein; however, PSI treatment of breast epithelial cells transfected with the p62 promoter did not affect promoter activity. High levels of prostate-derived Ets factor (PDEF) mRNA have been identified in breast cancer compared to normal breast. Only the PSA and maspin promoters have been identified as targets of this transcription factor. Here we show that PDEF stimulates the p62 promoter through at least two sites, and likely acts as a coactivator. PSI treatment abrogates the PDEF-stimulated increase of p62 promoter activity by 50%. Thus, multiple mechanisms for the induction of p62 exist. We conclude that (1) p62 protein is overexpressed in breast cancer; (2) p62 mRNA and protein increase in response to PSI, with no change of basal promoter activity; (3) PDEF upregulates p62 promoter activity through at least two sites; and (4) PSI downregulates PDEF-induced p62 promoter activation through one of these sites.
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PMID:p62 overexpression in breast tumors and regulation by prostate-derived Ets factor in breast cancer cells. 1270 Jun 67

New perspectives in prostate cancer genesis and putative clinical management have emerged in recent years . Apoptosis plays a major role in this environment. Proteasome inhibitors block the action of a multicatalytic proteinase complex involved in the degradation of intracellular proteins, particularly with regard to cell cycle regulation and apoptosis. Numerous in vitro studies have demonstrated the ability of these compounds to induce apoptosis and enhance the activity of conventional tumoricidal agents in many cancer cell types, including prostate cancer cells. They point out the use of these potent inhibitors as a new potential molecular approach to the therapeutic management of prostate cancer. Furthermore, the action of proteasome inhibitors has been tested in animal models and in patients with hormone refractory prostate cancer, resulting in both PSA and tumor volume decrease. PS-341 (bortezomib, Velcade) is the first proteasome inhibitor with clinical application in cancer therapy that has been used in clinical trials to date. This report reviews the current status of those papers that have tried to analyze the connection between the proteasome pathway and apoptosis. We present our results of proteasome inhibition in individual prostate cancer cell lines. Proteasomal inhibition may offer a new therapeutic access in "molecular targeting" of prostate cancer.
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PMID:[Proteasome inhibitors: induction of apoptosis as new therapeutic option in prostate cancer]. 1552 29

The study of mitotic transduction of the signal showed that overexpression of pAkt and reduction in pERK expression would be associated a biological relapse. For tumors T1-3 N0M0 at the high risk of local relapse after prostatectomy, an immediate radiotherapy compared with a differed radiotherapy (at the time of PSA relapse), showed a significant reduction in the rate of local relapse and an ameliorated progression free survival. The effectiveness of the docetaxel was confirmed in two phase III randomized clinical trials : TAX-327 with 3 arms compared docetaxel every 21 days, docetaxel every 7 days and mitoxantrone. All arms were prednisone-based. An increase in overall survival, PSA progression free survival, PSA response rate and a pain reduction were highlighted in the docetaxel arm every 21 days. Docetaxel obtained at the end of this study the marketing authorization in this indication and became the treatment of reference. The SWOG 99-16 study compared the docetaxel estramustine association with the same arm of reference, mitoxantrone and prednisone, with similar results. The addition of estramustine to the docetaxel seems to improve the PSA response rate and progression free survival, but with a greater embolic toxicity. The addition of an antiangiogenic agent, the thalidomide, to docetaxel, improves progression free survival and overall survival. PSA responses were observed with an inhibitor of the proteasome, the bortezomib, in monotherapy, contrary to the imatinib which in monotherapy didn't have any effectiveness. Studies in association with docetaxel are ongoing. Some biological responses were observed with a vaccine anti MUC-1 and must be confirmed on a greater series of patients. The docetaxel impact on localized disease is actually evaluated.
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PMID:[Prostate cancer: update]. 1626 70

Androgen receptor (AR) transactivation is known to enhance prostate cancer cell survival. However, the precise effectors by which the prosurvival effects of androgen and AR drive prostate cancer progression are poorly defined. Here, we identify a novel feed-forward loop involving cooperative interactions between ligand-activated AR and heat-shock protein 27 (Hsp27) phospho-activation that enhance AR stability, shuttling, and transcriptional activity, thereby increasing prostate cancer cell survival. Androgen-bound AR induces rapid Hsp27 phosphorylation on Ser(78) and Ser(82) residues in an AR- and p38 kinase-dependent manner. After this androgen-induced, non-nuclear phospho-activation, Hsp27 displaces Hsp90 from a complex with AR to chaperone AR into the nucleus and interact with its response elements to enhance its genomic activity. Inhibition of Hsp27 phosphorylation, or knockdown using the antisense drug OGX-427, shifted the association of AR with Hsp90 to MDM2, increased proteasome-mediated AR degradation, decreased AR transcriptional activity, and increased prostate cancer LNCaP cell apoptotic rates. OGX-427 treatment of mice bearing LNCaP xenografts transfected with an androgen-regulated, probasin-luciferase reporter construct resulted in decreased bioluminescence and serum PSA levels as pharmacodynamic readouts of AR activity, as well as AR, Hsp27, and Hsp90 protein levels in LNCaP tumor tissue. These data identify novel nongenomic mechanisms involving androgen, AR, and Hsp27 activation that cooperatively interact to regulate the genomic activity of AR and justify further investigation of Hsp27 knockdown as an AR disrupting therapeutic strategy in prostate cancer.
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PMID:Cooperative interactions between androgen receptor (AR) and heat-shock protein 27 facilitate AR transcriptional activity. 1797 89

Previously, we found a novel gene, nuclear receptor interaction protein (NRIP), a transcription cofactor that can enhance an AR-driven PSA promoter activity in a ligand-dependent manner in prostate cancer cells. Here, we investigated NRIP regulation. We cloned a 413-bp fragment from the transcription initiation site of the NRIP gene that had strong promoter activity, was TATA-less and GC-rich, and, based on DNA sequences, contained one androgen response element (ARE) and three Sp1-binding sites (Sp1-1, Sp1-2, Sp1-3). Transient promoter luciferase assays, chromatin immunoprecipitation and small RNA interference analyses mapped ARE and Sp1-2-binding sites involved in NRIP promoter activation, implying that NRIP is a target gene for AR or Sp1. AR associates with the NRIP promoter through ARE and indirectly through Sp1-binding site via AR-Sp1 complex formation. Thus both ARE and Sp1-binding site within the NRIP promoter can respond to androgen induction. More intriguingly, NRIP plays a feed-forward role enhancing AR-driven NRIP promoter activity via NRIP forming a complex with AR to protect AR protein from proteasome degradation. This is the first demonstration that NRIP is a novel AR-target gene and that NRIP expression feeds forward and activates its own expression through AR protein stability.
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PMID:Nuclear receptor interaction protein, a coactivator of androgen receptors (AR), is regulated by AR and Sp1 to feed forward and activate its own gene expression through AR protein stability. 1798 71

Kallikrein-related peptidase 3 (KLK3, also known as prostate-specific antigen, PSA) is a chymotrypsin-like kallikrein that has anti-angiogenic properties. We have previously shown in a human umbilical vein endothelial cell (HUVEC) model that the anti-angiogenic effect of KLK3 is related to its enzyme activity. However, the mechanism of this effect remains to be clarified. To this end, we used a DNA microarray to study KLK3-induced changes in gene expression associated with reduction of HUVEC tube formation. Among the 41,000 genes studied, 311 were differentially expressed between control and KLK3-treated cells. These changes were enriched in several pathways, including those associated with proteasome, ubiquitin-mediated proteolysis, focal adhesion and regulation of the actin cytoskeleton. Furthermore, the changes were opposite to those previously described to occur during tubulogenesis. In conclusion, our results show that KLK3 induces gene expression changes in HUVECs. Although these changes might be relevant for the mechanism by which KLK3 exerts its anti-angiogenic activity, it cannot be judged from the present results whether they reflect the primary mechanism mediating the effect of KLK3 or are secondary to morphogenic differentiation.
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PMID:Gene expression changes associated with the anti-angiogenic activity of kallikrein-related peptidase 3 (KLK3) on human umbilical vein endothelial cells. 1862 92

In response to hormonal stimuli, a cascade of hierarchical post-translational modifications of nuclear receptors are required for the correct expression of target genes. Here, we show that the transcription factor TFIIH, via its cdk7 kinase, phosphorylates the androgen receptor (AR) at position AR/S515. Strikingly, this phosphorylation is a key step for an accurate transactivation that includes the cyclic recruitment of the transcription machinery, the MDM2 E3 ligase, the subsequent ubiquitination of AR at the promoter of target genes and its degradation by the proteasome machinery. Impaired phosphorylation disrupts the transactivation, as observed in cells either overexpressing the non-phosphorylated AR/S515A, isolated from xeroderma pigmentosum patient (bearing a mutation in XPD subunit of TFIIH), or in which cdk7 kinase was silenced. Indeed, besides affecting the cyclic recruitment of the transcription machinery, the AR phosphorylation defect favourizes to the recruitment of the E3 ligase CHIP instead of MDM2, at the PSA promoter, that will further attract the proteasome machinery. These observations illustrate how the TFIIH phosphorylation might participate to the transactivation by regulating the nuclear receptors turnover.
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PMID:The phosphorylation of the androgen receptor by TFIIH directs the ubiquitin/proteasome process. 2115 30

Signal transducer and activator of transcription 5 (Stat5) plays an important role in the transition of prostate cancer (PCa) to its castrate-resistant state. Pharmacologic targeting of Stat5 is a rational approach to delay castrate-resistant progression, in part, because Stat5 cooperates with the androgen receptor (AR) to promote PCa progression. Immunostaining of tissue microarrays was used to correlate Stat5 expression with Gleason grade and to characterize changes in treatment-naive and androgen-deprived human PCa. Potency of a Stat5 antisense oligonucleotide (ASO) on Stat5 knockdown, cell growth, and apoptosis was assessed in LNCaP, C4-2, and DU145 cells. Effects of Stat5 knockdown on AR activity and stability was assessed using a PSA transactivation-luciferase assay and cyclohexamide plus MG132 treatment, respectively. LNCaP tumor-bearing mice were castrated and randomly assigned to treatment with Stat5-ASO or controls. Here, we show that the frequency of Stat5 expression is significantly increased in high Gleason grade as well as in hormone-treated PCa. Also, specific knockdown of Stat5 with ASO abrogates androgen-induced AR nuclear translocation and PSA transactivation despite R1881 stimulation. Moreover, Stat5 knockdown destabilizes AR, which leads to AR degradation via the proteasome. Shown for the first time as a preclinical proof-of-principle, Stat5 knockdown with Stat5-ASO significantly delays CRPC tumor progression in vivo. Thereby, we are able to recapitulate our in vitro results by reducing serum PSA and expression levels of target proteins in the xenograft tumors.
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PMID:Transcription factor Stat5 knockdown enhances androgen receptor degradation and delays castration-resistant prostate cancer progression in vivo. 2121 33

We previously showed that Stattic V (Stat3 inhibitory compound V) reduces human sperm motility and cellular ATP levels, increases intracellular Ca(2+) concentration, and promotes mitochondrial membrane depolarization resulting in increased levels of extracellular reactive oxygen species (ROS). As these alterations in cellular function are highly similar to what is observed in a cell undergoing apoptosis, our goal was to determine if the immobilizing effect of Stattic V on spermatozoa results from apoptosis or was because of an oxidative stress. To address this question, spermatozoa were incubated with Stattic V in combination with a caspase inhibitor, a proteasome inhibitor or a cell permeant ROS scavenger. Following incubation in different conditions, sperm motility was evaluated by CASA, acrosomal integrity by FITC conjugated Pisum sativum agglutinin (PSA-FITC) labeling, intracellular pH, and mitochondrial superoxide production by flow cytometry using BCECF and MitoSoxRed dye, respectively. Levels of reduced thiols were assessed by iodoacetamidofluorescein staining on total and on sperm surface proteins, and protein tyrosine phosphorylation was evaluated by western blot. The loss in sperm motility induced by Stattic V was associated with a slight intracellular acidification and an important increase in intracellular superoxide anion. Unlike caspase and proteasome inhibitors, low molecular weight thiols, such as N-acetyl-L-cysteine (NAC), prevented Stattic V-induced sperm immobilization and increase responsiveness to acrosome reaction inducers. NAC also efficiently prevented the production of superoxide anion, mitochondrial membrane depolarization, intracellular acidification and the oxidation of protein free thiols caused by Stattic V. These results show that the deleterious effects of Stattic V on sperm functions are caused directly or indirectly by excessive intracellular ROS production without causing sperm apoptosis or necrosis.
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PMID:The immobilization of human spermatozoa by STAT3 inhibitory compound V results from an excessive intracellular amount of reactive oxygen species. 2653 48


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