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:3.4.21.73 (urokinase-type plasminogen activator)
10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our work was undertaken to compare the relative efficiency of 2 purified prostatic kallikreins, namely, hK2 and prostate-specific antigen (PSA or hK3), in the activation of single-chain urokinase (scuPA). We found that hK2 converts scuPA into an active enzyme with an efficiency equal to approximately 1/50 that of plasmin. During the activation of scuPA by hK2, two fragments of 33 and 22 kDa were generated. The NH2-terminal amino acid sequence of the 33 kDa fragment showed that hK2 cleaved scuPA between Lys158 and Ile159. In contrast to a previous report by another group, our purified hK3 preparation containing no trypsin-like contaminants was totally unable to activate scuPA. Our results show that kallikrein hK2 has plasmin-like activity and suggest that it could be the initiator of a proteolytic cascade leading to prostatic cancer invasion.
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PMID:Prostatic kallikrein hK2, but not prostate-specific antigen (hK3), activates single-chain urokinase-type plasminogen activator. 918 Jan 62

The precursor or zymogen form of prostate-specific antigen (pro-PSA) is composed of 244 amino acid residues including an amino-terminal propiece of 7 amino acids. Recombinant pro-PSA was expressed in Escherichia coli, isolated from inclusion bodies, refolded, and purified. The zymogen was readily activated by trypsin at a weight ratio of 50:1 to generate PSA, a serine protease that cleaves the chromogenic chymotrypsin substrate 3-carbomethoxypropionyl-L-arginyl-L-prolyl-L-tyrosine-p-nitroanili ne- HCl (S-2586). In this activation, the amino-terminal propiece Ala-Pro-Leu-Ile-Leu-Ser-Arg was released by cleavage at the Arg-Ile peptide bond. The recombinant pro-PSA was also activated by recombinant human glandular kallikrein, another prostate-specific serine protease, as well as by a partially purified protease(s) from seminal plasma. The recombinant PSA was inhibited by alpha1-antichymotrypsin, forming an equimolar complex with a molecular mass of approximately 100 kDa. The recombinant PSA failed to activate single chain urokinase-type plasminogen activator, in contrast to the recombinant hK2, which readily activated single chain urokinase-type plasminogen activator. These results indicate that pro-PSA is converted to an active serine protease by minor proteolysis analogous to the activation of many of the proteases present in blood, pancreas, and other tissues. Furthermore, PSA is probably generated by a cascade system involving a series of precursor proteins. These proteins may interact in a stepwise manner similar to the generation of plasmin during fibrinolysis or thrombin during blood coagulation.
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PMID:Characterization of the precursor of prostate-specific antigen. Activation by trypsin and by human glandular kallikrein. 926 Nov 79

Prostate specific antigen (uPSA) was purified to homogeneity from human urine using SuperQ-Toyopearl, Sulfate-Cellulofine, Phenyl-Toyopearl, CM-Sepharose, anti-urokinase IgG Sepharose and Sephadex G-100. The purified uPSA gave a major band at 32.9 kDa on SDS-PAGE under the reduced condition. However, it shows multiple bands on native PAGE. Substrate specificity of purified uPSA is identical with that of PSA from human seminal plasma and uPSA shows the kallikrein and chymotrypsin-like activities. On the analysis of N-terminal amino acid, two amino acid residues at N-terminal position of uPSA were detected and other amino acid sequence of uPSA was identical with that of sPSA. In addition, we isolated the multiple components of uPSA using anion-exchange chromatography. They were almost the same in amino acid composition and N-terminal amino acid sequences and showed differences in lectin-blotting pattern.
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PMID:Purification and characterization of prostate specific antigen from human urine. 936 70

Mechanisms causing negative findings of serum C-reactive protein (CRP) in inflammatory disorders and malignant neoplasms were investigated. Patients with advanced prostate cancer manifesting negative CRP and alpha 2M deficiency were found. This finding suggests that alpha 2M, a carrier protein of interleukin-6, mediates CRP synthesis by the liver. Mechanism of synthesis of acute phase proteins including CRP, SAA and others was shown to be different in response to inflammation, alpha 2M-dependence in alpha 2M deficiency, the production of CRP and SAA by human hepatoma cells (HepG2) and the processes on the transcriptional activation of acute phase protein genes. In cases of prostate cancer associated with serum alpha 2M deficiency metastasis to the bones was noted. This finding suggests that alpha 2M inhibits metastasis of prostate cancer. It was suggested that the alpha 2M deficiency develops from complex formation of alpha 2M with proteases including PSA and u-PA, and accelerated catabolism of the complex rather than suppressed production of alpha 2M.
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PMID:[Immunological background of plasma protein abnormalities--the relation between inflammation and malignant neoplasm]. 1059 Jun 64

Tumor markers are molecules that indicate the presence of malignancy. They are potentially useful in cancer screening, aiding diagnosis, assessing prognosis, predicting in advance a likely response to therapy, and monitoring patients with diagnosed disease. Because of the low prevalence of most cancers in the general population and the limited sensitivity and specificity of available markers, these tests alone are generally of little value in screening for cancer in healthy subjects. Currently, however, PSA in combination with digital rectal examination and CA 125 together with ultrasound are undergoing evaluation as screening modalities for prostate and ovarian cancer, respectively. Again, because of a lack of sensitivity and specificity, markers are rarely of use in the early diagnosis of cancer. As prognostic indicators, markers may provide information that is independent of traditionally used factors or within subgroups defined by traditional criteria, for example, urokinase plasminogen activator in node-negative breast cancer. At present, the best available marker for predicting response to therapy is the estrogen receptor for selecting hormone-sensitive breast cancers. Many different markers can be used in the surveillance of patients with diagnosed malignancies, the most useful of these being HCG in trophoblastic disease and both AFP and HCG for nonseminomatous testicular germ cell tumors. In general, the currently available tumor markers lack sensitivity for early cancer and specificity for malignancy. The goal of future research should be to develop more sensitive and specific markers, especially for the common cancers.
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PMID:Clinical uses of tumor markers: a critical review. 1145 Dec 9

u-PA contributes to CaP progression, especially in the metastatic androgen-insensitive state. In vitro, u-PA is expressed by androgen-insensitive, but not androgen-sensitive, CaP cell lines. We hypothesized that in androgen-sensitive CaP an activated ARE represses u-PA expression but in androgen-insensitive CaP this repression is lost and u-PA is upregulated through MAP kinase signaling pathways. To determine whether binding of the DHT-AR complex to AREs in the u-PA promoter region represses u-PA transcription in androgen-sensitive CaP, we studied 2 PC3 androgen-insensitive human CaP cell lines stably transfected with AR [PC3(AR)(2) and PC3(AR)(13)] and 1 mock-transfected cell line [PC3(M)]. In the presence of the synthetic androgen mibolerone, both PC3(AR)(2) and PC3(AR)(13), but not PC3(M), cells showed decreased u-PA expression as assayed by Western and Northern blotting. The AR inhibitor flutamide abrogated mibolerone's effect. Androgen regulation of a second gene, PSA, was also demonstrated in the PC3(AR)(2) cell line. To explore the pathway stimulating u-PA expression in CaP, we performed transient transfections in PC3(AR)(2) cells using u-PA promoter-regulated CAT reporter constructs. Compared to full-length u-PA promoter-CAT constructs, either deletion or mutation of the 5' AP-1 or PEA3 site reduced CAT expression. The location of androgen responsiveness in the u-PA promoter was not identified through the combination of promoter search and transient transfection assays, indicating that a more complicated mechanism is involved in the AR-mediated downmodulation of u-PA expression.
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PMID:Regulation of u-PA gene expression in human prostate cancer. 1174 19

Prostate cancer (PC) develops as a consequence of abnormal androgenic stimulation. Unfortunately, most of the PC cell lines are androgen independent (like DU145), or express mutated forms of androgen receptor (AR). We have produced and characterized a new stably transfected PC line expressing the AR (DU145-AR). Untreated DU145-AR cells showed a lower proliferation rate than mock transfected cells, but responded to testosterone treatment. PSA mRNA, undetectable in mock DU145 cells, was present and upregulated by testosterone in DU145-AR. About 5% of DU 145-AR cells showed modification of morphology and enriched of f-actin after testosterone treatment. Moreover, in DU145-AR plasminogen activator (PA) activity and secreted urokinase type plasminogen activator (uPA) protein were lower than in AR negative cells; again testosterone induced PA activity and uPA protein only in DU145-AR. These results indicate that, in general, the effects of unactivated AR is to suppress function(s) in DU145 cells and the addition of testosterone restores the normal properties associated with the untransfected cells. Some of the effects described may thus be mediated by a ligand-independent activation of AR in DU145 cells.
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PMID:Characterization of prostate cancer DU145 cells expressing the recombinant androgen receptor. 1464 44

After therapeutic hormone deprivation, most prostate cancer (PrCa) cells develop androgen-independent (AI) growth. PrCa is highly heterogeneous and multifocal, suggesting that several molecular processes or pathways may be contributing to AI. The human LuCaP 23.1 xenograft model retains clinical hallmarks of PrCa, including heterogeneous growth, PSA production, androgen-responsiveness and progression to AI. In this work, we studied the effect of androgen depletion (castration) on the growth of LuCaP 23.1 xenografts. A total of 100 nude mice were implanted and analysed for their growth profiles before and after castration. By 11 and 15 weeks, tumours were harvested and assessed for molecular marker expression specific for PrCa. Prior to castration we found 37 fast growing (FG) tumours (948.9+/-76.9 mm(3)) and 63 slow growing (SG) tumours (229.6+/-18.4 mm(3)), a previously undescribed result for this PrCa model. Quantitative RT-PCR showed that in comparison to SGs, FGs contained high HER1, uPA and thymidilate synthetase (TS) expression with low levels of 5alpha-reductase 2 mRNA. All FG tumours progressed rapidly to AI growth 5 weeks after castration (FG-P). In SG castrated tumours, 66% of tumours (SG-P) showed retarded progression (by 12 weeks) to AI, whereas 34% responded to castration (SG-R). Molecular analysis permitted us to define distinct molecular profiles integrating different pathways associated with AI progression. FG-P, and a subgroup of SG-P tumours, presented significantly high levels of peptidylglycine alpha-amidating monooxygenase (PAM), HER1, HER2, TS, and uPA mRNA, all of which correlated with AR expression. The second subgroup of SG-P tumours showed overexpression of the antiapoptotic gene Bcl-2. A third subgroup of SG-P tumours showed significant expression of hypoxia-related gene (adrenomedullin) after castration. This work permitted to define distinct molecular profiles related to different AI growth in the LuCaP 23.1 xenograft.
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PMID:Molecular analysis integrating different pathways associated with androgen-independent progression in LuCaP 23.1 xenograft. 1548 89

The plasminogen activation system is involved in cancer progression and metastasis. Among other proteolytic factors, it includes the serine protease urokinase-type plasminogen activator (uPA) and its three-domain (D1D2D3) receptor uPAR (CD87), which focuses plasminogen activation to the cell surface. The function of uPAR is regulated in part through shedding of domain D1 by proteases, e.g., uPA itself or plasmin. Human tissue kallikrein 4 (hK4), which is highly expressed in prostate and ovarian tumor tissue, was previously shown to cleave and activate the pro-enzyme forms of prostate-specific antigen (PSA, tissue kallikrein hK3) and uPA. Here we demonstrate that uPAR is also a target for hK4, being cleaved in the D1-D2 linker sequence and, to a lesser extent, in its D3 juxtamembrane domain. hK4 may thus modulate the tumor-associated uPA/uPAR-system activity by either activating the pro-enzyme form of uPA or cleaving the cell surface-associated uPA receptor.
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PMID:Interplay of human tissue kallikrein 4 (hK4) with the plasminogen activation system: hK4 regulates the structure and functions of the urokinase-type plasminogen activator receptor (uPAR). 1649 55

Overexpression of urokinase-type plasminogen activator receptors (uPAR) represents an important biomarker for aggressiveness in most common malignant diseases, including prostate cancer (PC). Accordingly, uPAR expression either assessed directly in malignant PC tissue or assessed directly in plasma (intact/cleaved forms)-provides independent additional clinical information to that contributed by PSA, Gleason score, and other relevant pathological and clinical parameters. In this respect, non-invasive molecular imaging by positron emission tomography (PET) offers a very attractive technology platform, which can provide the required quantitative information on the uPAR expression profile, without the need for invasive procedures and the risk of missing the target due to tumor heterogeneity. These observations support non-invasive PET imaging of uPAR in PC as a clinically relevant diagnostic and prognostic imaging method. In this review, we will focus on the recent development of uPAR PET and the relevance within prostate cancer imaging. Novel antibody and small-molecule radiotracers-targeting uPAR, including a series of uPAR-targeting PET ligands, based on the high affinity peptide ligand AE105, have been synthesized and tested in vitro and in vivo in preclinical murine xenograft models and, recently, in a first-ever clinical uPAR PET study in cancer patients, including patients with PC. In this phase I study, a high and specific uptake of the tracer ⁶⁴Cu-DOTA-AE105 was found in both primary tumors and lymph node metastases. The results are encouraging and support large-scale clinical trials to determine the utility of uPAR PET in the management of patients with PC with the goal of improving outcome.
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PMID:PET imaging of urokinase-type plasminogen activator receptor (uPAR) in prostate cancer: current status and future perspectives. 2793 81


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