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)

Human seminal plasma contains high concentrations of prostatic acid phosphatase (PAP), prostate-specific antigen (PSA), beta-microseminoprotein (MSP), semenogelin I (SgI), and semenogelin II (SgII), whereas only PAP and MSP are present in rodents. In order to gain a better understanding of the evolution and function of semen proteins, we have studied ejaculates from the common marmoset (Callithrix jacchus)-a New World monkey. Semen samples were analyzed with SDS-PAGE, Western blotting, and isoelectric focusing. Under reducing conditions the dominating protein components appear as heterogeneous material of 55-70 kDa and distinct protein bands of 85, 17, 16, and 15 kDa. The heterogeneous material contains glycosylated material detected by an antiserum recognizing both human SgI and SgII. Southern blotting indicates that the common marmoset has genes for both SgI and SgII. There are several marmoset MSP genes, but the strong immunoreactivity against one 15 kDa semen component with pI 7.3 suggests preferential expression of one gene in the prostate. Expression of two other genes cannot be excluded as indicated by weak reaction to isoforms with pI 6.6 and 4.9. Unexpectedly, PSA was not detected by either immunological methods or activity measurements. This is in agreement with results from Southern blotting suggesting that the common marmoset might not have a PSA gene. Thus, in this study we have shown that semen coagulum proteins are present in marmoset seminal plasma, but the lack of PSA precludes a similar liquefaction as of human semen.
Mol Reprod Dev 2005 Jun
PMID:Ejaculates from the common marmoset (Callithrix jacchus) contain semenogelin and beta-microseminoprotein but not prostate-specific antigen. 1579 87

The serine protease inhibitor (serpin) protein C inhibitor (PCI) has been found in the prostate and possibly is a marker to distinguish normal prostate, benign prostatic hyperplasia, and prostate cancer. In this study, we assessed PCI expression in normal, hyperplastic, and malignant prostatic tissues, prostate cancer cell lines, and the CWR22 prostate cancer xenograft model that allowed us to study PCI expression and its regulation in response to androgens. By Northern blot, immunohistochemistry, and in situ hybridization, we found that PCI was expressed in both benign and malignant prostate tissues. Protein C inhibitor was expressed in both androgen-independent (PC-3) and androgen-dependent (LNCaP) prostate cancer cell lines. Furthermore, PCI was detected in all CWR22 tumor samples (androgen dependent, 6 days post-castration, 12 days post-castration followed by 72 h of testosterone treatment, and recurrent CWR22 tumor), although expression of the mature forms of both prostate-specific antigen (PSA) and its homolog, kallikrein 2 (hK2), was clearly androgen-dependent. These results suggest that PCI expression is not regulated by androgens and that PCI is unlikely to be a tumor suppressor gene, but also that PCI may be involved in regulating key serine proteases involved in metastatic prostate disease.
Exp Mol Pathol 2005 Aug
PMID:Protein C inhibitor (plasminogen activator inhibitor-3) expression in the CWR22 prostate cancer xenograft. 1587 12

In the current study, expression of the apoptotic calcium channel receptor P2X(7) and prostate-specific antigen (PSA) levels were studied in biopsy cores from 174 patients as well as 20 radical prostatectomy cases. In clinical biopsies, we have previously demonstrated that P2X(1 )and P2X(2) calcium channel receptors are absent from normal prostate epithelium that does not progress to prostate cancer within 5 years. In cases that did progress to prostate cancer however, P2X(1 )and P2X(2) labeling was observed in a stage-specific manner first in the nucleus, then the cytoplasm and finally on the apical epithelium, as prostate cancer developed. These markers were present up to 5 years before cancer was detectable by the usual morphological criteria (Gleason grading) as determined by H and E staining. In the current study, the apoptotic calcium channel receptor P2X(7) yielded similar results to that of P2X(1) and P2X(2). Using radical prostatectomy tissue sections as well as biopsies, these changes in calcium channel metabolism were noted throughout the prostate, indicating a field effect. This finding suggests that the presence of a prostate tumor could be detected without the need for direct sampling of tumor tissue, leading to detection of false negative cases missed by H or E stain. The reliability of PSA levels as a prognostic indicator has been questioned in recent years. In the current study, PSA levels were correlated with the P2X(7) labeling results. All patients who exhibited no P2X(7) labeling had a prostatic serum antigen (PSA) level of <2. Patients who exhibited stage-specific P2X(7) expression, and who later developed obvious prostate cancer as diagnosed by H and E stain, all had a PSA > 2. This finding suggests that increasing PSA may be an accurate indicator of cancer development.
J Mol Histol 2005 Mar
PMID:Expression of the apoptotic calcium channel P2X7 in the glandular epithelium. 1590 Apr 5

Our previous report showed that methylseleninic acid (MSA) significantly decreases the expression of androgen receptor and prostate-specific antigen (PSA) in LNCaP cells. The present study extended the above observations by showing the universality of this phenomenon and that the inhibitory effect of MSA on prostate cancer cell growth and cancer-specific biomarkers is mediated through androgen receptor down-regulation. First, MSA decreases the expression of androgen receptor and PSA in five human prostate cancer cell lines (LNCaP, LAPC-4, CWR22Rv1, LNCaP-C81, and LNCaP-LN3), irrespective of their androgen receptor genotype (wild type versus mutant) or sensitivity to androgen-stimulated growth. Second, by using the ARE-luciferase reporter gene assay, we found that MSA suppression of androgen receptor transactivation is accounted for primarily by the reduction of androgen receptor protein level. Third, MSA inhibition of five androgen receptor-regulated genes implicated in prostate carcinogenesis (PSA, KLK2, ABCC4, DHCR24, and GUCY1A3) is significantly attenuated by androgen receptor overexpression. Fourth, transfection of androgen receptor in LNCaP cells weakened noticeably the inhibitory effect of MSA on cell growth and proliferation. Androgen receptor signaling has been documented extensively to play an important role in the development of both androgen-dependent and -independent prostate cancer. Our finding that MSA reduces androgen receptor availability by blocking androgen receptor transcription provides justification for a mechanism-driven intervention strategy in using selenium to control prostate cancer progression.
Mol Cancer Ther 2005 Jul
PMID:Androgen receptor signaling intensity is a key factor in determining the sensitivity of prostate cancer cells to selenium inhibition of growth and cancer-specific biomarkers. 1602 Jun 62

Proteomic analysis of formalin-fixed paraffin-embedded (FFPE) tissue would enable retrospective biomarker investigations of this vast archive of pathologically characterized clinical samples that exist worldwide. These FFPE tissues are, however, refractory to proteomic investigations utilizing many state of the art methodologies largely due to the high level of covalently cross-linked proteins arising from formalin fixation. A novel tissue microdissection technique has been developed and combined with a method to extract soluble peptides directly from FFPE tissue for mass spectral analysis of prostate cancer (PCa) and benign prostate hyperplasia (BPH). Hundreds of proteins from PCa and BPH tissue were identified, including several known PCa markers such as prostate-specific antigen, prostatic acid phosphatase, and macrophage inhibitory cytokine-1. Quantitative proteomic profiling utilizing stable isotope labeling confirmed similar expression levels of prostate-specific antigen and prostatic acid phosphatase in BPH and PCa cells, whereas the expression of macrophage inhibitory cytokine-1 was found to be greater in PCa as compared with BPH cells.
Mol Cell Proteomics 2005 Nov
PMID:Proteomic analysis of formalin-fixed prostate cancer tissue. 1609 76

Androgen receptor plays a critical role in the development of primary as well as advanced hormone-refractory prostate cancer. Therefore, ablation of androgen receptor from prostate cancer cells is an interesting concept for developing a new therapy not only for androgen-dependent prostate cancer but also for metastatic hormone-refractory prostate cancer, for which there is no effective treatment available. We report here that LAQ824, a cinnamyl hydroxamatic acid histone deacetylase inhibitor currently in human clinical trials, effectively depleted androgen receptor in prostate cancer cells at nanomolar concentrations. LAQ824 seemed capable of depleting both the mutant and wild-type androgen receptors in either androgen-dependent and androgen-independent prostate cancer cells. Although LAQ824 may exert its effect through multiple mechanisms, several lines of evidence suggest that inactivation of the heat shock protein-90 (Hsp90) molecular chaperone is involved in LAQ824-induced androgen receptor depletion. Besides androgen receptor, LAQ824 reduced the level of Hsp90 client proteins HER-2 (ErbB2), Akt/PKB, and Raf-1 in LNCaP cells. Another Hsp90 inhibitor, 17-allyamino-17-demethoxygeldanamycin (17-AAG), also induced androgen receptor diminution. LAQ824 induced Hsp90 acetylation in LNCaP cells, which resulted in inhibition of its ATP-binding activity, dissociation of Hsp90-androgen receptor complex, and proteasome-mediated degradation of androgen receptor. Consequently, LAQ824 blocked androgen-induced prostate-specific antigen production in LNCaP cells. LAQ824 effectively inhibited cell proliferation and induced apoptosis of these prostate cancer cells. These results reveal that LAQ824 is a potent agent for depletion of androgen receptor and a potential new drug for prostate cancer.
Mol Cancer Ther 2005 Sep
PMID:Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824. 1617 22

Recently it has become clear that more potent methods for DNA vaccine delivery need to be developed to enhance the efficacy of DNA vaccines. In vivo electroporation has emerged as a potent method for DNA vaccine delivery. In a mouse model, we evaluated the CD8(+) T lymphocyte response to a prostate cancer DNA vaccine encoding prostate-specific antigen (PSA) after intradermal electroporation. A significantly increased gene expression (100- to 1000-fold) and higher levels of PSA-specific T cells, compared to DNA delivery without electroporation, was demonstrated. Interestingly, investigation of a panel of different electroporation conditions showed that only some conditions that induce high levels of gene expression additionally induced cellular immunity. This suggests that electroporation parameters should be carefully optimized, not only to enhance transfection efficiency, but also to enhance the immune response to the vaccine. This study demonstrates the applicability of intradermal electroporation as a delivery method for genetic cancer vaccines and other DNA vaccines relying on antigen-specific T cell induction.
Mol Ther 2006 Feb
PMID:Enhancement of cellular immune response to a prostate cancer DNA vaccine by intradermal electroporation. 1618 33

Numerous mouse models of prostate carcinogenesis have been developed, but hitherto there has been no model in which the prostate gland could be imaged in live animals. The transgenic model generated here targeted mouse prostate gland using a firefly luciferase enzyme under the control of a small but highly active and specific supra prostate-specific antigen (sPSA) promoter. We evaluated postnatal prostate development, involution and androgen-induced restoration of prostate growth in adult transgenic mice using bioluminescence imaging. Results of our study showed that: (i) the prostate gland of male offspring did not yield a significant bioluminescence signal until after sexual maturity. Luciferase was detected in the luminal epithelial cells of the ventral and dorsolateral lobes of the prostate gland and caput epididymis, with little or no activity in 18 other organs evaluated. (ii) While a constant high level of bioluminescence was detected in the mouse prostate from 5 to 35 weeks of age, a slight drop in bioluminescence was detected at 36 to 54 weeks. (iii) Upon castration, the luciferase activity signal associated with mouse prostate detected by a cooled charge-coupled device camera was dramatically reduced. This signal could be rapidly restored to pre-castration levels after androgen administration. Androgen-induced luciferase activity subsided to nearly basal levels 5 days following the last injection. These data demonstrate that a bioluminescent mouse model with luciferase activity restricted to the prostate gland under the control of a (sPSA) promoter can be used on a real-time basis in live animals to investigate the development and responsiveness of the prostate gland to exogenously administered androgen. This model can be extended to detect the responsiveness of the prostate gland to therapy and used as a founder strain to visualize tumors in hosts with different genetic backgrounds.
J Mol Endocrinol 2005 Oct
PMID:A luciferase transgenic mouse model: visualization of prostate development and its androgen responsiveness in live animals. 1621 10

The current understanding of the response of androgen receptor to pharmacologic inhibitors in prostate cancer is derived primarily from serum prostate-specific antigen (PSA) levels. In this study, we test whether a novel androgen receptor-specific molecular imaging system is able to detect the action of the antiandrogen flutamide on androgen receptor function in xenograft models of prostate cancer. Adenoviruses bearing an optical imaging cassette containing an androgen receptor-responsive two-step transcriptional amplification system were injected into androgen-dependent and hormone-refractory tumors of animals undergoing systemic time-controlled release of the antiandrogen flutamide. Imaging of tumors with a cooled charge-coupled device camera revealed that the response of AdTSTA to flutamide is more sensitive and robust than serum PSA measurements. Flutamide inhibits the androgen signaling pathway in androgen-dependent but not refractory tumors. Analysis of androgen receptor and RNA polymerase II binding to the endogenous PSA gene by chromatin immunoprecipitation revealed that flutamide treatment and androgen withdrawal have different molecular mechanisms. The application of imaging technology to study animal models of cancer provides mechanistic insight into antiandrogen targeting of androgen receptor during disease progression.
Mol Cancer Ther 2005 Nov
PMID:Imaging androgen receptor function during flutamide treatment in the LAPC9 xenograft model. 1627 87

Activation of signal transduction kinase cascades is known to alter androgen receptor (AR) activity, but the molecular mechanisms are still poorly defined. Here we show that stress kinase signaling regulates Ser 650 phosphorylation and AR nuclear export. In LNCaP prostate cancer cells, activation of either MAPK kinase (MKK) 4:c-Jun N-terminal kinase (JNK) or MKK6:p38 signaling pathways increased Ser 650 phosphorylation, whereas pharmacologic inhibition of JNK or p38 signaling led to a reduction of AR Ser 650 phosphorylation. Both p38alpha and JNK1 phosphorylated Ser 650 in vitro. Small interfering RNA-mediated knockdown of either MKK4 or MKK6 increased endogenous prostate-specific antigen (PSA) transcript levels, and this increase was blocked by either bicalutamide or AR small interfering RNA. Stress kinase inhibition of PSA transcription is, therefore, dependent on the AR. Similar experiments involving either activation or inhibition of MAPK/ERK kinase:ERK signaling had little effect on Ser 650 phosphorylation or PSA mRNA levels. Ser 650 is proximal to the DNA binding domain that contains a nuclear export signal. Mutation of Ser 650 to alanine reduced nuclear export of the AR, whereas mutation of Ser 650 to the phosphomimetic amino acid aspartate restored AR nuclear export. Pharmacologic inhibition of stress kinase signaling reduced wild-type AR nuclear export equivalent to the S650A mutant without affecting nuclear export of the S650D mutant. Our data suggest that stress kinase signaling and nuclear export regulate AR transcriptional activity.
Mol Endocrinol 2006 Mar
PMID:Stress kinase signaling regulates androgen receptor phosphorylation, transcription, and localization. 1628 70


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