Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to understand the androgen-related factors which may regulate concentrations of the tumour marker, prostate-specific antigen (PSA). We therefore measured the serum concentrations of total and free testosterone and of sex hormone-binding globulin (SHBG) and determined the androgen receptor (AR) gene CAG repeat length, then compared these values to total and free PSA concentrations in 91 subjects with proven fertility, and 112 subfertile men with defective spermatogenesis. Concentrations of free testosterone and total testosterone, adjusted for SHBG, were 17-20% lower in subfertile men compared with those in their fertile counterparts. This subtle, but highly significant (P < 0.001), difference in testosterone between fertile and subfertile men was accentuated by the positive correlation between testosterone and AR gene CAG repeat length in fertile, but not subfertile, subjects. In subfertile subjects, testosterone strongly correlated (r = 0.354, P < 0.001) with PSA concentrations, and independent of testosterone, total PSA negatively correlated (r = -0.229, P = 0.011) with AR CAG length. Overall our data suggest that, firstly, PSA correlates with testosterone only in an environment of relatively low androgenicity, such as in subfertile men. Secondly, in such a low androgenic environment, short CAG tracts (associated with high AR activity) correlate positively with PSA concentrations. These results suggest that interpretation of PSA is best made in conjunction with testosterone concentrations and AR CAG length.
Mol Hum Reprod 2001 Nov
PMID:Prostate-specific antigen, testosterone, sex-hormone binding globulin and androgen receptor CAG repeat polymorphisms in subfertile and normal men. 1167 66

The bombesin/gastrin-releasing peptide (GRP) family of neuropeptides has been implicated in various in vitro and in vivo models of human malignancies including prostate cancers. It was previously shown that bombesin and/or neurotensin (NT) acts as a survival and migratory factor(s) for androgen-independent prostate cancers. However, a role in the transition from an androgen-dependent to -refractory state has not been addressed. In this study, we investigate the biological effects and signal pathways of bombesin and NT on LNCaP, a prostate cancer cell line which requires androgen for growth. We show that both neurotrophic factors can induce LNCaP growth in the absence of androgen. Concurrent transactivation of reporter genes driven by the prostate-specific antigen promoter or a promoter carrying an androgen-responsive element (ARE) indicate that growth stimulation is accompanied by androgen receptor (AR) activation. Furthermore, neurotrophic factor-induced gene activation was also present in PC3 cells transfected with the AR but not in the parental line which lacks the AR. Given that bombesin does not directly bind to the AR and is known to engage a G-protein-coupled receptor, we investigated downstream signaling events that could possibly interact with the AR pathway. We found that three nonreceptor tyrosine kinases, focal adhesion kinase (FAK), Src, and Etk/BMX play important parts in this process. Etk/Bmx activation requires FAK and Src and is critical for neurotrophic factor-induced growth, as LNCaP cells transfected with a dominant-negative Etk/BMX fail to respond to bombesin. Etk's activation requires FAK, Src, but not phosphatidylinositol 3-kinase. Likewise, bombesin-induced AR activation is inhibited by the dominant-negative mutant of either Src or FAK. Thus, in addition to defining a new G-protein pathway, this report makes the following points regarding prostate cancer. (i) Neurotrophic factors can activate the AR, thus circumventing the normal growth inhibition caused by androgen ablation. (ii) Tyrosine kinases are involved in neurotrophic factor-mediated AR activation and, as such, may serve as targets of future therapeutics, to be used in conjunction with current antihormone and antineuropeptide therapies.
Mol Cell Biol 2001 Dec
PMID:Neuropeptide-induced androgen independence in prostate cancer cells: roles of nonreceptor tyrosine kinases Etk/Bmx, Src, and focal adhesion kinase. 1171 75

Prostate-specific antigen (PSA), a 237-amino acid glycoprotein, encoded by the hKLK3 gene, is widely used as a serum marker for the diagnosis and management of prostate cancer. We report here the localization of a conformational epitope recognized by the anti-total PSA monoclonal antibody (mAb) 11E5C6, by proteolytic degradation of mAb-bound antigen followed by mass spectrometric analyses of the peptides generated. These two technologies, combined with molecular display, allowed the identification of amino acid residues contained within three different peptides distant on the PSA sequence, but close in the PSA three-dimensional structure, that may be part of the mAb 11E5C6 epitope. The last four C-terminal amino acid residues are included in this epitope, as well as certain other C-terminal residues between Y225 and T232. The involvement of the PSA C-terminal end in the mAb 11E5C6 epitope was confirmed by western blotting experiments with the recombinant protein proPSA-RP1, resulting from the cloning of an alternative transcript of the hKLK3 gene, in which the PSA C-terminal end was deleted and replaced by another sequence. Although the anti-total PSA mAb 5D5A5 used as a control bound proPSA-RP1, mAb 11E5C6 did not. The requirement of the C-terminal end for the recognition by mAb 11E5C6 may be useful for the discrimination of PSA-related forms.
J Mol Recognit
PMID:Involvement of the C-terminal end of the prostrate-specific antigen in a conformational epitope: characterization by proteolytic degradation of monoclonal antibody-bound antigen and mass spectrometry. 1175 74

Gene therapy is founded on the concept that tissue-specific promoters can express heterologous genes for molecular imaging or therapeutic applications. The engineering of cell-specific enhancers to improve potency and the development of two-step transcriptional activation (TSTA) approaches have significantly improved the efficacy of transgene expression. Here we combine these technologies to create a robust, titratable, androgen-responsive system targeted to prostate cancer cells. Our "chimeric" TSTA system uses a duplicated variant of the prostate-specific antigen (PSA) gene enhancer to express GAL4 derivatives fused to one, two, or four VP16 activation domains. We targeted the resulting activators to cells with reporter templates bearing one, two, or five GAL4 binding sites upstream of firefly luciferase. We monitored activity via firefly luciferase assays in transfected cell extracts and in live nude mice using a cooled charge-coupled device (CCD) imaging system. In this system, we found that firefly luciferase expression in prostate cancer cells can be varied over an 800-fold range. We also found that a single plasmid bearing the optimized enhancer, GAL4-VP16 derivative, and reporter expressed firefly luciferase at 20-fold higher levels than the cytomegalovirus enhancer. We discuss the implications of this strategy and its application to molecular imaging and therapy.
Mol Ther 2002 Mar
PMID:Molecular engineering of a two-step transcription amplification (TSTA) system for transgene delivery in prostate cancer. 1186 11

The organization of the human tissue kallikrein gene family has now been fully elucidated. This family contains 15 genes encoding secreted serine proteases, which share significant homologies at both the DNA and amino acid level. Two members of the human kallikrein gene family, prostate-specific antigen and human kallikrein 2, have already found important clinical application as prostate cancer biomarkers. In this review, we examine the diagnostic and prognostic value of the 15 human kallikrein genes and proteins. It is clear that at least a few members show promise of becoming novel cancer and other disease biomarkers.
Expert Rev Mol Diagn 2001 Jul
PMID:Human tissue kallikrein gene family: a rich source of novel disease biomarkers. 1190 13

The transcription factor NF-kappa B regulates gene expression involved in cell growth and survival and has been implicated in progression of hormone-independent breast cancer. By expressing a dominant-active form of mitogen-activated protein kinase kinase kinase 1, by exposure to tumor necrosis factor alpha, or by overexpression of p50/p65, we show that NF-kappa B activates a transcription regulatory element of the prostate-specific antigen (PSA)-encoding gene, a marker for prostate cancer development, treatment, and progression. By DNase I footprinting, we identified four NF-kappa B binding sites in the PSA core enhancer. We also demonstrate that androgen-independent prostate cancer xenografts have higher constitutive NF-kappa B binding activity than their androgen-dependent counterparts. These results suggest a role of NF-kappa B in prostate cancer progression.
Mol Cell Biol 2002 Apr
PMID:NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer. 1190 78

Prostate cancer is the second-leading cause of cancer-related deaths in men in the United States. Unfortunately, there is no effective therapy when prostate cancer becomes metastatic and refractory to conventional treatments. For this reason, the identification and exploration of new agents that reduce prostate cancer cell growth are of paramount importance. High consumption of plant-derived phytoestrogens is inversely associated with the incidence and mortality rate of prostate cancer. Previous studies, including our own, have shown that the phytoestrogen genistein inhibits prostate cancer cell growth in vitro and in vivo and decreases secreted and intracellular levels of the androgen-regulated protein prostate-specific antigen (PSA), but the role of genistein as an agonist/antagonist for hormone receptors remains unclear. To elucidate the mechanism by which genistein modulates PSA protein expression in prostate cancer cells, we investigated the effects of genistein on androgen-mediated and estrogen-mediated transcriptional regulation of PSA, androgen receptor (AR) mRNA and protein expression, and the ability of nuclear proteins to bind to androgen-response elements (AREs) in LNCaP cells. We showed that genistein decreased the transcriptional activation of PSA by both androgen-dependent and androgen-independent methods in LNCaP cells. The reduction of androgen-mediated transcriptional activation of PSA was correlated with decreased AR protein and mRNA levels and decreased binding to AREs. In contrast, genistein had differential effects on 17beta-estradiol-mediated PSA expressions. Low concentrations of genistein enhanced 17beta-estradiol-mediated PSA expressions, whereas high concentrations of genistein inhibited estrogen-mediated PSA expression in LNCaP cells. Genistein did not inhibit AR protein expression in the presence of 17beta-estradiol. These results suggest that ligand-dependent differences in the ability to activate PSA expression may contribute to the agonistic/antagonistic responses observed with genistein in prostate cancer cells.
Mol Carcinog 2002 Jun
PMID:Expression of prostate-specific antigen is transcriptionally regulated by genistein in prostate cancer cells. 1211 15

Prostate-specific kallikrein, a member of the gene family of serine proteases, was initially discovered in semen and is the most useful serum marker for prostate cancer diagnosis and prognosis. We report the crystal structure at 1.42A resolution of horse prostate kallikrein (HPK). This is the first structure of a serine protease purified from seminal plasma. HPK shares extensive sequence homology with human prostate-specific antigen (PSA), including a predicted chymotrypsin-like specificity, as suggested by the presence of a serine residue at position S1 of the specificity pocket. In contrast to other kallikreins, HPK shows a structurally distinct specificity pocket. Its entrance is blocked by the kallikrein loop, suggesting a possible protective or substrate-selective role for this loop. The HPK structure seems to be in an inactivated state and further processing might be required to allow the binding of substrate molecules. Crystal soaking experiments revealed a binding site for Zn(2+) and Hg(2+), two known PSA inhibitors.
J Mol Biol 2002 Sep 13
PMID:Crystal structure of a prostate kallikrein isolated from stallion seminal plasma: a homologue of human PSA. 1221 94

The expression of prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA), two well characterized marker proteins, remains highly active in the hormone refractory stage of prostate cancer. In this study, an artificial chimeric enhancer (PSES) composed of two modified regulatory elements controlling the expression of PSA and PSMA genes was tested for its promoter activity and tissue specificity using the reporter system. As a result, this novel PSES promoter remained silent in PSA- and PSMA-negative prostate and non-prostate cancer cell lines, but mediated high levels of luciferase in PSA- and PSMA-expressing prostate cancer cell lines in the presence and absence of androgen. To determine whether PSES could be used for in vivo gene therapy of prostate cancer, a recombinant adenovirus, Ad-PSES-luc, was constructed. Luciferase activity in prostate cancer cell lines mediated by Ad-PSES-luc was 400- to 1000-fold higher than in several other non-prostate cell lines, suggesting the high tissue-specificity of the PSES promoter in an adenoviral vector. Finally, recombinant virus Ad-PSES-luc was injected into mice to evaluate the tissue-discriminatory promoter activity in an experimental animal. Unlike Ad-CMV-luc, the luciferase activity from systemic injection of Ad-PSES-luc was fairly low in all major organs. However, when injected into prostate, Ad-PSES-luc drove high luciferase activity almost exclusively in prostate and not in other tissues. Our results demonstrated the potential use of PSES for the treatment of androgen-independent prostate cancer patients.
Mol Ther 2002 Sep
PMID:Novel prostate-specific promoter derived from PSA and PSMA enhancers. 1223 Nov 79

Interleukin-6 (IL-6) is a multifunctional cytokine which is involved in regulation of growth of various malignant tumors. IL-6 binds to its receptor, which is composed of a ligand-binding and a signal-transducing subunit and activates pathways of signal transducers and activators of transcription and mitogen-activated protein kinases (MAPKs). In prostate cancer cells, IL-6 induces divergent proliferative responses. Serum levels of IL-6 are elevated in patients with therapy-resistant carcinoma of the prostate. We have investigated whether IL-6 interacts with the androgen signaling pathway in prostate cancer cells. In DU-145 cells, transiently transfected with androgen receptor (AR) cDNA, IL-6 caused ligand-independent and synergistic activation of the AR. Nonsteroidal antagonists of the AR down-regulated AR activity induced by IL-6. In LNCaP cells, IL-6-induced expression of the AR-regulated prostate-specific antigen gene. Inhibitors of protein kinase A and C and MAPK down-regulated IL-6-induced AR activity. IL-6 expression in human prostate tissue was studied by immunohistochemistry. In benign prostatic tissue, IL-6 immunoreactivity was confined to basal cells. In prostate intraepithelial neoplasia and in cancer tissue, atypical intraluminal and cancer cells expressed IL-6. The expression of IL-6 receptor was demonstrated in benign and malignant tissue in both epithelium and stroma. In the authors' laboratory, IL-6-inhibited proliferation of parental LNCaP cells. A new LNCaP subline was generated to investigate changes in signal transduction which might occur after prolonged treatment with IL-6. In the subline LNCaP-IL-6+, IL-6 neither reduced a number of cells nor caused G1 growth arrest. IL-6 receptor expression declined during long-term IL-6 treatment. However, IL-6-up-regulated AR expression and was capable of inducing AR activity in LNCaP-IL-6+ cells. Parental LNCaP cells do not express IL-6. In contrast, IL-6 mRNA and protein expression were detectable in high passages of LNCaP-IL-6+ cells. Thus changes in signal transduction occur in prostate cancer cells after prolonged IL-6 treatment
Mol Cell Endocrinol 2002 Nov 29
PMID:Interleukin-6 regulates androgen receptor activity and prostate cancer cell growth. 1243 17


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