Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1519176 (PSA)
 5,490 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate-specific human glandular kallikrein (hK2) is an active enzyme in human seminal fluid. It is one of three serine proteases in the human kallikrein gene family, which includes hK1 (tissue kallikrein) and hK3 (prostate-specific antigen [PSA]). In order to examine kininogenase activity (i.e., production of kinin by these enzymes), we tested for bradykinin and/or Lys-bradykinin release upon incubation of hK2 and for other kallikreins with high-molecular weight kininogen (HMWK), which contains the nonapeptide bradykinin. Kinins are important regulatory peptides (especially for vascular permeability), and they may have a role in enhancing sperm motility. High-molecular weight kininogen is the substrate for plasma kallikrein (PKa potent kinin-generating enzyme circulating in blood, not of the same gene family) and for hK1. Glandular kallikrein and protein-C inhibitor (PCI)-hK2 complex, a serpin protease inhibitor that binds hK2, were purified to homogeneity by affinity and size-exclusion chromatography. About one-half of the hK2 is found in complex with PCI. The kallikrein enzymes were incubated with HMWK, and the resulting cleavage products were analyzed for kinin activity using enzyme immunoassay, high-performance liquid chromatography and mass spectrometry, and in vitro bioassay. Our results show that hK2 cleaves HMWK to produce bradykinin, not Lys-bradykinin (like hK1), and the resultant heavy (56-kDa) and light (42-kDa) chains of HMWK show similar electrophoretic mobility to those cleaved by PK. Prostate-specific antigen (hK3) had no kinin-generating activity. We also identified three other internal cleavage sites for hK2 in HMWK (Arg427, Arg437, and Arg457) that yielded two peptides, one of which is identical to a PK-cleaved peptide. Glandular kallikrein is about 500-fold less active than is PK or tissue kallikrein, but it may play a physiologically important role in bradykinin release in seminal fluid.
 ...
PMID:Kininogenase activity of prostate-derived human glandular kallikrein (hK2) purified from seminal fluid. 1023 57

The gene of tissue kallikrein and closely related genes constitute the glandular kallikrein (GK) gene family. The number of members varies between species, ranging from three human to 25 murine. Recently, the gene family was extended with 12 new members, KLK4-KLK15, that were identified adjacent to the classical GK genes on human chromosome 19. In this report, the structure and phylogeny of the mouse GK gene locus are described. A comparison of the human and murine loci shows that the locations of the tissue kallikrein gene and KLK4-KLK15 are conserved. The region between the tissue kallikrein gene and KLK15, devoid of genes in human, is expanded and contains 23 classical GK genes in mouse. Downstream of KLK15, where the genes encoding PSA and hK2 are located in human, mouse carries the pseudogene PsimGK25. Phylogenetic analyses show that classical GK genes emerged after the separation of the primate and rodent lineages, forming a subgroup within the newly extended GK family.
 ...
PMID:Organization and evolution of the glandular kallikrein locus in Mus musculus. 1243 87

Serine proteases are proteolytic enzymes with an active serine residue in their catalytic site. Kallikreins are a subgroup of the serine protease family and are known to have diverse physiological functions. The human tissue kallikrein gene family has now been fully characterized and includes 15 members, clustered in a 300 kb region on chromosome 19q13.4. In this review, we discuss the common structural features of kallikreins at the DNA, mRNA and protein levels. Kallikreins are secreted as inactive zymogens and are activated by cleavage of an N-terminal peptide. Some kallikreins can undergo autoactivation while others may be activated by other kallikreins or other proteases. Most kallikreins are predicted to have trypsin-like enzymatic activity except for three members which may have chymotrypsin-like activity. Circumstantial evidence suggests that at least some kallikreins may be part of an enzymatic cascade pathway which is activated in aggressive forms of ovarian and probably other cancers. Accumulating evidence suggests potential diagnostic and/or prognostic roles of kallikreins in diverse malignancies. In addition to PSA, many other kallikreins show differential expression in malignancy. For example, hK6, 10 and 11 are promising serological markers for ovarian cancer diagnosis. KLK10 may act as a tumor suppressor. In addition to their diagnostic and prognostic values, kallikreins may also be good therapeutic targets.
 ...
PMID:Tissue kallikreins: new players in normal and abnormal cell growth? 1287 20

In a previous study we demonstrated that repeated duplications of the tissue kallikrein gene (Klk1) had resulted in 24 paralogs in mouse. Here we demonstrate a different evolution of rat glandular kallikrein genes. Repeated duplications of an approximately 30-kb region, encompassing Klk1, Klk15, and Klk2-ps, resulted in 10 copies of each gene, but only the Klk1 paralogs are functional. The number of genes varies also between nonrodent mammals, e.g., there are probably no paralogs to KLK1 in cow and pig, whereas horse could have up to 5. In the dog, the gene encoding the prostatic arginine esterase was identified as an ortholog to the progenitor of the PSA and hK2 genes, and it carries the same conserved androgen-responsive elements directing prostate transcription as these genes. This is highly interesting with respect to animal models of benign prostate hyperplasia and prostate adenocarcinoma--diseases that have been described only in humans and dogs.
 ...
PMID:Taxon-specific evolution of glandular kallikrein genes and identification of a progenitor of prostate-specific antigen. 1520 12

Human tissue kallikrein genes, located on the long arm of chromosome 19, are a subgroup of the serine protease family of proteolytic enzymes. Initially thought to consist of three members, the human kallikrein locus has now been extended and includes 15 tandemly located genes. These genes, and their protein products, share a high degree of homology and are expressed in a wide array of tissues, mainly those that are under steroid hormone control. PSA (hK3) is one of the human kallikreins, and is the most useful tumor marker for prostate cancer screening, diagnosis, prognosis and monitoring. hK2, another prostate-specific kallikrein, has also been proposed as a complementary prostate cancer biomarker. In the past 5 years, the newly discovered kallikreins (KLK4-KLK15) have been associated with several types of cancer. For example, hK4, hK5, hK6, hK7, hK8, hK10, hK11, hK13 and hK14 are emerging biomarkers for ovarian, breast, prostate and testicular cancer. New evidence raises the possibility that some kallikreins are directly involved with cancer progression. We here review the evidence linking kallikreins and cancer and their applicability as novel biomarkers for cancer diagnosis and management.
 ...
PMID:Human tissue kallikrein gene family: applications in cancer. 1591 Oct 97

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.
 ...
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

Human tissue kallikreins (hKs) form a family of 15 closely related (chymo)trypsin-like serine proteinases. These tissue kallikreins are expressed in a wide range of tissues including the central nervous system, the salivary gland, and endocrine-regulated tissues, such as prostate, breast, or testis, and may have diverse physiological functions. For several tissue kallikreins, a clear correlation has been established between expression and different types of cancer. For example, the prostate-specific antigen (PSA or hK3) serves as tumor marker and is used to monitor therapy response. Using a novel strategy, we have cloned, expressed in Escherichia coli or in insect cells, refolded, activated, and purified the seven human tissue kallikreins hK3/PSA, hK4, hK5, hK6, hK7, hK10, and hK11. Moreover, we have determined their extended substrate specificity for the nonprime side using a positional scanning combinatorial library of tetrapeptide substrates. hK3/PSA and hK7 exhibited a chymotrypsin-like specificity preferring large hydrophobic or polar residues at the P1 position. In contrast, hK4, hK5, and less stringent hK6 displayed a trypsin-like specificity with strong preference for P1-Arg, whereas hK10 and hK11 showed an ambivalent specificity, accepting both basic and large aliphatic P1 residues. The extended substrate specificity profiles are in good agreement with known substrate cleavage sites but also in accord with experimentally solved (hK4, hK6, and hK7) or modeled structures. The specificity profiles may lead to a better understanding of human tissue kallikrein functions and assist in identifying their physiological protein substrates as well as in designing more selective inhibitors.
 ...
PMID:Specificity profiling of seven human tissue kallikreins reveals individual subsite preferences. 1674 Jun 31

Human tissue kallikreins (genes, KLKs; proteins, hKs) are a subgroup of hormonally regulated serine proteases. Two tissue kallikreins, namely hK2 and hK3 (prostate-specific antigen, PSA), are currently used as serological biomarkers of prostate cancer. Human tissue kallikrein 9 (KLK9) is a newly identified member of the tissue kallikrein gene family. Recent reports have indicated that KLK9 mRNA is differentially expressed in ovarian and breast cancer and has prognostic value. Here, we report the production of recombinant hK9 (classic form) using prokaryotic and mammalian cells and the generation of polyclonal antibodies. Total testis tissue mRNA was reverse-transcribed to cDNA, amplified, cloned into a pET/200 TOPO plasmid vector, and transformed into E. coli cells. hK9 was purified and used as an immunogen to generate polyclonal antibodies. Full-length KLK9 cDNA was also cloned in the vector pcDNA3.1 and was expressed in CHO cells. The identity of hK9 was confirmed by mass spectrometry. hK9 rabbit antiserum displayed no cross-reactivity with other tissue kallikreins and could specifically recognize E. coli- and CHO-derived hK9 on Western blots. hK9 was mainly detected in testis and seminal vesicles by Western blotting. The reagents generated here will help to define the physiological role of this tissue kallikrein and its involvement in human disease.
 ...
PMID:Human tissue kallikrein 9: production of recombinant proteins and specific antibodies. 1680 Jul 34

Human tissue kallikrein 4 (hK4) belongs to a 15-member family of closely related serine proteinases. hK4 is predominantly expressed in prostate, activates hK3/PSA, and is up-regulated in prostate and ovarian cancer. We have identified active monomers of recombinant hK4 besides inactive oligomers in solution. hK4 crystallised in the presence of zinc, nickel, and cobalt ions in three crystal forms containing cyclic tetramers and octamers. These structures display a novel metal site between His25 and Glu77 that links the 70-80 loop with the N-terminal segment. Micromolar zinc as present in prostatic fluid inhibits the enzymatic activity of hK4 against fluorogenic substrates. In our measurements, wild-type hK4 exhibited a zinc inhibition constant (IC50) of 16 microM including a permanent residual activity, in contrast to the zinc-independent mutants H25A and E77A. Since the Ile16 N terminus of wild-type hK4 becomes more accessible for acetylating agents in the presence of zinc, we propose that zinc affects the hK4 active site via the salt-bridge formed between the N terminus and Asp194 required for a functional active site. hK4 possesses an unusual 99-loop that creates a groove-like acidic S2 subsite. These findings explain the observed specificity of hK4 for the P1 to P4 substrate residues. Moreover, hK4 shows a negatively charged surface patch, which may represent an exosite for prime-side substrate recognition.
 ...
PMID:Crystal structures of human tissue kallikrein 4: activity modulation by a specific zinc binding site. 1695 Mar 94

Prostate cancer is associated with significant mortality once the tumour has spread outside the gland. Epithelial-mesenchymal transition (EMT) has been proposed to facilitate this dissemination of tumour cells. In this article we summarize the evidence for EMT in prostate cancer, drawing on the expression of EMT-related markers and the functions of factors known to induce EMT in other systems. We also discuss our recent findings that two members of the tissue kallikrein family of serine proteases, prostate-specific antigen (PSA/KLK3) and kallikrein-related peptidase 4 (KLK4), lead to EMT-like changes in PC3 prostate cancer cells.
 ...
PMID:Epithelial-mesenchymal transition in prostate cancer and the potential role of kallikrein serine proteases. 1758 16


1 2 Next >>