Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have isolated four cDNAs encoding the entire preproprotein of prostate specific antigen from human prostatic cDNA libraries. Comparison of the coding regions of prostate specific antigen with human pancreatic kallikrein (1-3) and human glandular kallikrein (4) showed 73%-84% nucleotide and 61-77% amino acid homologies, respectively, between these enzymes. Also the 3' noncoding regions of these genes were conserved. The close resemblance of prostate specific antigen, a marker for prostatic cancer, to glandular kallikrein suggests related immunogenic properties for them.
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PMID:cDNA coding for the entire human prostate specific antigen shows high homologies to the human tissue kallikrein genes. 247 Mar 73

The three dimensional structures of human prostate specific antigen (PSA) and glandular kallikrein (hGK) were modeled based on porcine pancreatic kallikrein A. High sequence similarity and conserved framework of serine proteases enabled accurate modeling. The catalytic site region consisting of catalytic triad, residues forming oxyanion hole and main-chain substrate binding residues were conserved. The substrate specificity pocket of PSA resembles that of chymotrypsin and hGK is most related with tonin. The models were used to predict interactions with substrate and inhibitor molecules. The models are valuable in interpreting mutant and epitope mapping data as well as when modifying properties of the proteases or when developing diagnostic detection methods for prostatic cancer.
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PMID:Modeling of prostate specific antigen and human glandular kallikrein structures. 752 61

Prostate-specific antigen (PSA) provides an excellent serum marker for prostate cancer, the most frequent form of cancer in American males. PSA is a 237-residue protease based on sequence homology to kallikrein-like enzymes. To predict the 3-dimensional structure of PSA, homology modeling studies were performed based on sequence and structural alignments with tonin, pancreatic kallikrein, chymotrypsin, and trypsin. The structurally conserved regions of the 4 reference X-ray proteins provided the core structure of PSA, whereas the loop structures were modeled on the loops of tonin and kallikrein. The unique "kallikrein loop" insert, between Ser 95b and Pro 95k of kallikrein, was constructed using molecular mechanics, dynamics, and electrostatics calculations. In the resulting PSA structure, the catalytic triad, involving residues His 57, Asp 102, and Ser 195, and hydrophobic and electrostatic interactions typical of serine proteases were extremely well conserved. Similarly, the 5-disulfide bonds of kallikrein were also conserved in PSA. These results, together with the fact that no major steric clashes arose during the modeling process, provide strong evidence for the validity of the PSA model. Calculation of the electrostatic potential contours of kallikrein and PSA was carried out using the finite difference Poisson-Boltzmann method. The calculations revealed matching areas of negative potential near the catalytic triad, but differences in the positive potential surrounding the active site. The PSA glycosylation site, Asn 61, is fully accessible to the solvent and is enclosed in a positive region of the isopotential map. The bottom of the substrate specificity pocket, residue S1, is a serine (Ser 189) as in chymotrypsin, rather than aspartate (Asp 189) as in tonin, kallikrein, and trypsin. This fact, plus other features of the S1 binding-pocket region, suggest that PSA would prefer substrates with hydrophobic residues at the P1 position. The location of a potential zinc ion binding site involving the side chain of histidines 91, 101, and 233 is also suggested. This PSA model should facilitate the understanding and prediction of structural and functional properties of this important cancer marker.
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PMID:A structural model for the prostate disease marker, human prostate-specific antigen. 753 13

Human prostate-specific antigen (PSA), a 33- to 34-kDa serine proteinase with extensive homology to glandular kallikrein, is a single-chain glycoprotein that contains 7% carbohydrate. The presence of PSA in the serum of patients with prostatic cancer is widely employed as a marker of disease status. PSA has also been thought of as a possible target for use in active specific immunotherapy protocols. To date, the source of PSA employed has been seminal fluid from different individuals; this has raised concerns about differences among PSA batches for standardization of assays. This report is the first description of the production and the purification of a recombinant source of PSA using a baculovirus expression system. A baculovirus recombinant of the cDNA encoding the full length PSA was expressed in insect cells yielding two major immunoreactive products of 31 and 29 kDa. The latter size conforms to the molecular weight of a core preprotein deduced from the sequence of the cDNA insert. The larger protein represents the N-linked glycosylated form of the preprotein. Western blot analysis showed that both the glycosylated and aglycosylated forms of PSA reacted with a polyclonal and two different monoclonal antibodies specific for PSA. bV-PSA, like commercially available PSA, showed also low-molecular-weight immunoreactive products when culture supernatants were concentrated or taken through steps of purification. bV-PSA was purified to a final product consisting of a major 29-kDa protein and a minor 31-kDa protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Generation, purification, and characterization of a recombinant source of human prostate-specific antigen. 756 44

Prostate-specific antigen (PSA) is a widely used marker for screening and monitoring prostate cancer. We identified and characterized the epitopes of two anti-PSA monoclonal antibodies (mAbs) designated B80 and B87. The epitopes were initially mapped as nonoverlapping by developing a sandwich immunoassay to measure PSA with the two anti-PSA mAbs. The two antibodies do not cross-react with homologous pancreatic kallikrein, but recognize epitopes unique to PSA. B80 and B87 can recognize both free and complexed PSA and hence measure total PSA. Epitope scanning and bacteriophage peptide library affinity selection procedures were used to identify and locate an epitope on PSA. A possible epitope for B80 was identified as being located on or near PSA amino acid residues 50-58 (-GRH-SLFHP-). The epitope for B87 was likely on an exposed nonlinear conformational determinant, unique to PSA, and not masked by the binding of B80 or alpha 1-antichymotrypsin.
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PMID:Epitope mapping of prostate-specific antigen with monoclonal antibodies. 896 33

A polymorphism in the human prostate-specific glandular kallikrein (hKLK2) gene was described by direct sequencing (by PCR) of genomic DNAs isolated from prostatic cancer tissue, benign prostatic hyperplasia tissue, and blood leukocyte specimens. Results showed two forms of human prostate-specific glandular kallikrein protein (hK2), a consequence of a change from C to T at base 792 in the hK2 coding region. Producing the two forms as recombinant proteins in insect cells demonstrated that Arg226-hK2 (CC genotype) is an active protein and Trp226-hK2 (TT genotype) is inactive. Polymorphism studies of 36 patients with prostatic diseases identified only 1 with the TT genotype. The same kind of polymorphism was not detected in the human prostate-specific antigen (hKLK3) gene. Arg226-hK2 possessed only trypsin-like enzyme activity, whereas recombinant human prostate-specific antigen (hPSA) had only chymotrypsin-like activity. Monoclonal and polyclonal antibodies raised against hPSA purified from seminal plasma detected both active and inactive hK2. Thus, because inactive as well as stable hK2 protein may be present, a lack of trypsin-like activity in hPSA standards is not enough to confirm that the materials are free of hK2 contamination.
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PMID:Human prostate-specific glandular kallikrein is expressed as an active and an inactive protein. 902 30

Human glandular kallikrein (hK2) protein, like prostate-specific antigen (PSA), is produced mainly in prostatic epithelium. It may be useful as a new diagnostic indicator for prostate cancer. Recently, a number of hK2-specific monoclonal antibodies have been developed that enable us to detect hK2 protein in human prostate tissue, seminal fluid, and sera. Whether hK2 can be expressed, like PSA, in nonprostatic cells is not known. In this study, we have characterized the presence of hK2 in an androgen-responsive breast cancer cell line T47-D at both the protein and mRNA levels with an immunoassay, Western blot analysis, Northern blot analysis, and the reverse transcription-PCR. Using a sensitive immunoassay with monoclonal antibodies to hK2, we found that T47-D cells could be induced with androgens, mineralocorticoids, glucocorticoids, and progestins to produce significantly more hK2 than PSA. Estrogens failed to mimic the effect of the other steroids, blocking instead the stimulatory effect of androgens. Androgen induction of hK2 in T47-D cells was dose dependent. More interestingly, we found that the hK2 in androgen-induced T47-D cell spent media appears to be the pro-form of hK2 rather than mature hK2. Our study demonstrates that hK2, a serine protease thought to be found only in prostate-related tissues and fluids, is also produced in a breast cancer cell line T47-D after steroid stimulation. This finding suggests that hK2 may have a potential role in breast cancer as well as prostatic cancer and will be the impetus for further studies of hK2 distribution and function.
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PMID:Expression of human prostate-specific glandular kallikrein protein (hK2) in the breast cancer cell line T47-D. 920 72

KLK1/tissue kallikrein is a member of a family of structurally related serine proteases which exhibit a diverse range of enzymic activities. Other members of this family of genes and the bradykinin (B2) receptor have been implicated in cancer processes. The KLK genes are expressed in various organs of the reproductive tract, including the prostate and uterus. In this study, we have examined whether KLK1/tissue kallikrein and the B2 receptor were both expressed in cancers emanating from these organs. We have shown that KLK1/tissue kallikrein and the B2 receptor are expressed, to varying degrees, in prostate disease and 2 human prostate cancer cell-lines, LNCaP and DU145. KLK1 is also expressed in a range of endometrial cancers, although at lower levels than that observed for normal human endometrial tissues. These findings suggest that a functional kallikrein-kinin system is present in prostate disease, in particular, which may be important in the process of tumorigenesis in this tissue.
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PMID:Tissue kallikrein and the bradykinin B2 receptor are expressed in endometrial and prostate cancers. 922 49

Two of the human tissue kallikrein family, hK2 and hK3 (prostate-specific antigen), are primarily produced by the prostatic epithelium under the regulation of androgens. In this study, we detected prostate cancer cells that expressed hKLK2 or hKLK3 mRNA in the peripheral blood of patients with prostate cancer using reverse transcription-PCR (RT-PCR). We then demonstrated some differences in characteristics, such as differentiation of cancer cells and response to antiandrogen therapy, between hKLK2 and hKLK3 mRNA-expressing prostate cancer cells. Total RNA was isolated from 41 patients with known prostate cancer, 7 patients with benign prostatic hyperplasia, and 20 normal volunteers. By RT-PCR, hKLK2 mRNA was detected in 7 patients (33%), and hKLK3 mRNA was detected in 17 (81%) of 21 stage D prostate cancer patients. In contrast, all patients with benign prostatic hyperplasia and healthy volunteers were negative. From comparison of the background of the patients positive for hKLK2 and/or hKLK3 mRNA, it became evident that the response to antiandrogen therapy and the expression of hKLK2 mRNA were reciprocally correlated, in contrast with the expression of hKLK3 mRNA. Additionally, our study clearly demonstrated that the detection of hKLK2 mRNA in the peripheral blood was useful for screening patients with certain prostate cancers that did not express hK3. We conclude that taking advantage of the difference between hKLK2 mRNA and hKLK3 mRNA expression is clinically useful for following up prostate cancer patients.
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PMID:Detection of prostate cancer cells circulating in peripheral blood by reverse transcription-PCR for hKLK2. 933 Oct 68

Human glandular kallikrein (hK2) is a possible new marker for prostate cancer that is homologous to prostate specific antigen. Purified hK2 added to serum or plasma reacted with endogenous protease inhibitors to form complexes of >350, 135, and 80 kDa, and some hK2 remained free, as judged by immunoblotting. The former two complexes could be removed by specific antibodies to alpha2-macroglobulin and to C1- inactivator, respectively, and they comigrated on SDS-PAGE with complexes formed between hK2 and purified alpha2-macroglobulin or C1-inactivator. hK2 complexes of 80 kDa could not be completely removed with any anti-serpin antibody used. Thus, these may consist of more than one type of hK2 complex. In contrast, essentially all hK2 complexes were removed from seminal plasma by antibody to protein C inhibitor, demonstrating that protein C inhibitor is the only significant inhibitor of hK2 in semen. hK2 reacted more rapidly with alpha2-macroglobulin than with any other inhibitor in plasma or serum. Divalent metal ions and heparin did not appreciably affect the rate of formation of any of the hK2 complexes in serum or plasma or with purified alpha2-macroglobulin or C1-inactivator. Measurement of one or more of the hK2 forms identified here may have diagnostic or prognostic potential for prostate cancer.
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PMID:alpha2-macroglobulin and C1-inactivator are plasma inhibitors of human glandular kallikrein. 985 94


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