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)

Using gene-specific synthetic oligonucleotides the expression and regulation of kallikrein-like genes in the human prostatic cancer cell line LNCaP were studied. Prostate-specific antigen (PSA) and human glandular kallikrein (hGK-1) together constitute a subfamily of serine proteases exclusively produced in the human prostate. RNA analysis revealed that both genes are expressed in LNCaP cells with PSA basal levels being 2-fold higher than hGK-1 levels. Both mRNAs are induced over a period of 24 h in the presence of 3.3 nM of the synthetic androgen mibolerone. Stimulation of PSA RNA is about 5-fold, whereas hGK-1 stimulation is less pronounced. Nuclear run-on analysis revealed that androgen induction of kallikrein-like genes in LNCaP cells is a rapid event (less than 3 h) occurring at the level of transcription initiation. Treatment of cells with cycloheximide demonstrates that, while PSA/hGK-1 basal transcription strictly depends on continuous protein synthesis, transcriptional induction by androgen does not. This suggests the direct involvement of the androgen receptor in the induction process independent of additional labile protein factors necessary for kallikrein basal transcription. A binding motif is present in the PSA and hGK-1 promoters, closely resembling the consensus sequence for steroid-responsive elements. The androgen antagonist cyproterone acetate was also able to stimulate transcription of kallikrein-like genes in LNCaP cells. In contrast, androgen-dependent transcriptional suppression of the protooncogene c-myc was strongly counteracted by cyproterone acetate. Thus, antiandrogens act differentially on androgen-regulated prostate-specific (PSA, hGK-1) and growth-related (c-myc) gene expression in LNCaP cells.
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PMID:Transcriptional regulation of prostate kallikrein-like genes by androgen. 137 10

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

Prostate-specific antigen (PSA) is a 33 kD protein synthesized in the epithelial cells of the prostate gland. It is a serine protease that belongs to the subgroup of kallikreins, among which it is very similar to a putative enzyme called human glandular kallikrein (hGK-1). Although the hGK-1 enzyme remains to be characterized in vivo, the hGK-1 gene is expressed in the same prostatic epithelial cells as the PSA gene. Expression of the PSA gene is under complex control and the steady-state level of PSA mRNA is increased by androgens, and decreased by epidermal growth factor and activation of protein kinase C. This suggests the existence of several regulatory elements within the cis-acting control elements of the PSA gene. As a seminal serine protease, PSA has been shown to digest the high molecular weight seminal vesicle protein, seminogelin. However, it is likely that this does not constitute the only natural substrate of PSA, as PSA has been shown to degrade insulin-like growth factor-binding protein-3. Serum PSA concentrations are frequently increased in patients with prostatic cancer, but this is also the case in patients with benign prostatic hyperplasia. Thus, PSA measurements alone are not useful as a screening tool for undiagnosed prostatic cancer. However, serum PSA concentrations can be successfully used together with other methods in diagnosing prostatic diseases and in monitoring the successfulness of treatments for prostatic cancer.
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PMID:Prostate-specific antigen and human glandular kallikrein: two kallikreins of the human prostate. 752 Nov 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

Without question, much has been learned about the glycoprotein PSA in recent years. By increasing our understanding of this tumor marker's biochemical and physiologic properties, we will be able to improve its clinical utility. The discovery of the various molecular forms of PSA represents a significant advancement. Knowing the concentration and ratio of these PSA forms will be valuable in deciding which patients require further evaluation with transrectal ultrasound and prostate biopsy and which men can be monitored safely without undergoing further invasive testing. This information will be most valuable in treating the patient with a mildly elevated serum PSA level. Although assays are not yet available to detect specifically hK2, the striking similarities of hK2 to PSA, including selective expression in the prostate, suggest that this marker may also prove useful in prostate cancer management. Indeed, a new era of PSA testing has been entered, and the entire field of prostate cancer will benefit.
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PMID:Molecular forms of prostate-specific antigen and the human kallikrein gene family: a new era. 753 36

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

The genomic and the cDNA clones of human glandular kallikrein (hK2), a member of the kallikrein family, have been isolated; however, the hK2 protein has not yet been identified and characterized. The deduced sequence of hK2 is highly homologous to prostate specific antigen (PSA), a widely accepted prognostic indicator of prostate carcinoma. Also, hK2 mRNA, like PSA mRNA, is exclusively expressed in prostatic epithelia. These two properties make hK2 a potentially useful marker for studying prostate cancer. In this paper, we describe for the first time the overexpression of the entire hK2 protein (pre-pro hK2:pphK2) in the E. coli system. Our system yields high levels of authentic pphK2 (as determined by partial amino acid sequence analysis) comprising about 40% of total cellular protein. pphK2 was purified to near homogeneity by preparative SDS/PAGE and used to generate anti-pphK2 antibodies in rabbits. The antibodies recognize the recombinant hK2 protein and a major band of approximately 34 kDa in seminal fluid.
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PMID:Overexpression of a human prostate-specific glandular kallikrein, hK2, in E. coli and generation of antibodies. 766 87

Prostate-specific antigen (PSA), produced by prostate cells, provides an excellent serum marker for prostate cancer. It belongs to the human kallikrein family of enzymes, a second prostate-derived member of which is human glandular kallikrein-1 (hK2). Active PSA and hK2 are both 237-residue kallikrein-like proteases, based on sequence homology. An hK2 model structure based on the serine protease fold is presented and compared to PSA and six other serine proteases in order to analyze in depth the role of the surface-accessible loops surrounding the active site. The results show that PSA and hK2 share extensive structural similarity and that most amino acid replacements are centered on the loops surrounding the active site. Furthermore, the electrostatic potential surfaces are very similar for PSA and hK2. PSA interacts with at least two serine protease inhibitors (serpins): alpha-1-antichymotrypsin (ACT) and protein C inhibitor (PCI). Three-dimensional model structures of the uncleaved ACT molecule were developed based upon the recent X-ray structure of uncleaved antithrombin. The serpin was docked both to PSA and hK2. Amino acid replacements and electrostatic complementarities indicate that the overall orientation of the proteins in these complexes is reasonable. In order to investigate PSA's heparin interaction sites, electrostatic computations were carried out on PSA, hK2, protein C, ACT, and PCI. Two heparin binding sites are suggested on the PSA surface and could explain the enhanced complex formation between PSA and PCI, while inhibiting the formation of the ACT-PSA complex, PSA, hK2, and their preliminary complexes with ACT should facilitate the understanding and prediction of structural and functional properties for these important proteins also with respect to prostate diseases.
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PMID:Structural investigation of the alpha-1-antichymotrypsin: prostate-specific antigen complex by comparative model building. 873 55

The human kallikrein family consists of three members, hK1, hK2, and hK3 [prostate-specific antigen (PSA)]. PSA is a widely accepted marker for prostate cancer. The mRNAs for both hK2 and PSA are localized predominantly to prostate epithelium and are regulated by androgens. In addition, hK2 has 78% amino acid homology to PSA. Although similarities to PSA make hK2 a potential prostate cancer marker, they also impede biochemical characterization of hK2 in those human tissues and body fluids where PSA is abundant. To study the expression, biosynthesis, and processing of hK2, recombinant hK2 was expressed in the adenovirus-induced Syrian hamster tumor cell line AV12-664 (AV12-hK2). Expression of hK2 was analyzed by Western blots and ELISA using monoclonal antibodies HK1G 464.3 [specific for prohK2 (phK2)] and HK1D 106.4 [specific for phK2 and mature hK2 (hK2)1. Western blot and ELISA analyses showed that phK2 was secreted into the media by AV12-hK2 cells on day 1 and was gradually converted to the mature form of hK2 by day 7. N-terminal amino acid sequencing verified the Western blot and ELISA data. This demonstrates for the first time that hK2 is secreted as phK2 and converted to hK2 extracellularly. In addition, hK2 detected in day 4-7 AV12-hK2-spent media was enzymatically active. Recombinant hK2 was also expressed in human prostate carcinoma cell lines, PC3 (PC3-hK2) and DU145 (DU145-hK2), that do not express endogenous hK2 or PSA. Similar to AV12-hK2 cells, both cell lines secreted phK2 that was converted to hK2 extracellularly. phK2 was the major form detected in the spent media of PC3-hK2 cells, even after 7 days, indicating a slow conversion of phK2 to hK2. hK2 was the predominant form detected in the spent media of DU145-hK2 starting on day 1, indicating the rapid conversion of phK2 to hK2. In this study, we demonstrate that hK2 exists in different forms and is secreted as phK2. phK2 is then converted to enzymatically active hK2 extracellularly.
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PMID:Expression of human glandular kallikrein, hK2, in mammalian cells. 896 92

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


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