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)

Two forms of the same commercial product (SORBIAL, Allonnes, France), one with live bacteria (PSA) and the other with heat-inactivated bacteria (PSI), containing a mixture of 2 strains of lactobacilli and their growth medium were tested as a diet complement for juvenile sea bass (Dicentrarchus labrax) during a 103-day experiment. In addition to zootechnical parameters (survival, growth, conformation), some effects on digestive metabolism were studied, including enzymatic, ultrastructural and microbial aspects. Microbial preparations improved survival rate. The ventral, dorsal and operculum malformations which usually occur in juveniles did not appear in those receiving PSA and PSI. Furthermore, they stimulated, but not constantly, trypsin and acid phosphatase activities. Intestinal ultrastructure showed an increase in the number of endocytosis vesicles at the apical pole of enterocytes in fishes receiving enrichments. Bacterial flora was not modified in terms of quantity, especially the lactic acid bacteria counts, which were not changed in fishes receiving live lactobacilli (PSA). The mode of action of these multiple beneficial effects appears complex and could be caused by different molecules inside the bacterial cell or excreted into their medium.
J Mol Microbiol Biotechnol 2008
PMID:Preliminary study of the effects of commercial lactobacilli preparations on digestive metabolism of juvenile sea bass (Dicentrarchus labrax). 1795 16

Human prostate-specific antigen (PSA or KLK3) is an important marker for the diagnosis and management of prostate cancer. This is an androgen-regulated glycoprotein of the kallikrein-related protease family secreted by prostatic epithelial cells. Its physiological function is to cleave semenogelins in the seminal coagulum and its enzymatic activity is strongly modulated by zinc ions. Here we present the first crystal structure of human PSA in complex with monoclonal antibody (mAb) 8G8F5 that enhances its enzymatic activity. The mAb recognizes an epitope composed of five discontinuous segments including residues from the kallikrein loop and stabilizes PSA in an "open and active conformation" that accelerates catalysis. We also present the crystal structure of PSA in complex with both the mAb 8G8F5 and a fluorogenic substrate Mu-KGISSQY-AFC, derived from semenogelin I. By exploiting the inhibition of PSA by zinc ions, we were able to obtain a substrate acyl intermediate covalently linked to the catalytic serine, at pH 7.3 but not at pH 5.5. Moreover, the inhibition of PSA activity by zinc was found to be modulated by pH variations but not by the antibody binding. The correlation of the different data with the physiological conditions under which PSA can cleave semenogelins is discussed.
J Mol Biol 2008 Feb 29
PMID:Crystal structure of a ternary complex between human prostate-specific antigen, its substrate acyl intermediate and an activating antibody. 1818 50

Seeking insight into the possible role of estrogens in prostate cancer (PCa) evolution, we assayed serum E2, estrone (E1), and estrone sulfate (E1S) in 349 PCa and 100 benign prostatic hyperplasia (BPH) patients, and in 208 control subjects in the same age range (50-74 years). E1 (pmol/L+/-S.D.) and E1S (nmol/L+/-S.D.) in the PCa and BPH patients (respectively 126.1+/-66.1 and 2.82+/-1.78, and 127.8+/-56.4 and 2.78+/-2.12) were significantly higher than in the controls (113.8+/-47.6 and 2.11+/-0.96). E2 was not significantly different among the PCa, BPH, and control groups. These assays were also carried out in PCa patients after partition by prognosis (PSA, Gleason score (GS), histological stage, and surgical margins (SM)). Significantly higher E1S levels were found in PCa with: PSA>10 ng/L (3.05+/-1.92) versus PSA<or=10 ng/mL (2.60+/-1.55), stage pT3-T4 (2.99+/-1.80) versus pT2 (2.58+/-1.58), and positive (3.26+/-1.95) versus negative margins (2.52+/-1.48). E1 was higher in poor- than in better-prognosis PCa. E2 was significantly higher in PCa with GS>or=4+3 (109.5+/-43.8) versus GS<or=3+4 (100.6+/-36.5) and increased significantly when GS increased from 3+3 to 4+4. Estrogens, especially E1S appeared to be possible markers of PCa progression. Attempting to identify potential sources of E2 in PCa according to prognosis, as well as in BPH, we found a significant correlation coefficient between E1S and E2 (0.266-0.347) in poor-prognosis PCa and no correlation in BPH (0.026) and better-prognosis PCa (0.013-0.104). It is as though during progression of PCa from good to poor prognosis there were a shift in the E1 to E2 metabolic pathway from predominantly oxidative to predominantly reductive.
J Steroid Biochem Mol Biol 2008 Mar
PMID:Estrone sulfate (E1S), a prognosis marker for tumor aggressiveness in prostate cancer (PCa). 1833 90

Most prostate cancers escape endocrine therapy by diverse mechanisms. One of them might be growth repression by androgen. We reported that androgen represses the growth in culture of MOP cells (a sub-line of LNCaP cells) and that of MOP cell xenografts, although tumor growth becomes androgen-independent (AI). Here we explore whether AI tumors contain androgen-responsive cells. ME carcinoma cells were established from AI tumors. The responses to androgen were examined by cell counting, DAPI labeling, flow cytometry, PSA immunoassay and tumor size follow-up. Androgen receptors (AR) were analyzed by western blotting and DNA sequencing. The pattern of responses of these cells to androgen was compared to that of MOP cells and that of JAC cells established from LNCaP-like MOP cells. R1881, a synthetic androgen: (1) repressed the growth of all the six ME cell lines obtained, MOP and JAC cells, (2) augmented the secretion of PSA, (3) induced spectacular cell bubbling/fragmentation and (4) blocked the cell cycle and induced a modest increase of apoptosis. All the androgen-repressed cells expressed the same level of mutated AR as LNCaP cells. In nude mice, the growth of ME-2 cell xenografts displayed transient androgen repression similar to that of MOP cells. In culture neither fibroblasts nor extra-cellular matrix altered the effects of R1881 on cell proliferation. These results demonstrate that androgen-independent tumors contain androgen-responsive cells. The apparent discrepancy between the responses to androgen of tumors and those of carcinoma cells in culture suggests that microenvironmental factors contribute to the androgen responsiveness of tumor cells in vivo. These modifications, albeit unspecified, could be suitable targets for restoring the androgen responsiveness of AI tumors.
J Steroid Biochem Mol Biol 2008 Jul
PMID:Androgen inhibits the growth of carcinoma cell lines established from prostate cancer xenografts that escape androgen treatment. 1855 Mar 62

PrLZ is a novel recent isolated gene and specific expression in prostate tissues. PrLZ expression was specifically elevated in prostate embryonic tissues and androgen independent prostate cancer cells, suggesting it might be association with the embryonic development and malignancy progression. However, the function and mechanism of PrLZ during the progression of prostate cancer remain blurred. Our present studies showed PrLZ expression might enhance the proliferation and invasion capability in vitro and also increase the tumorigenicity in situ prostate cancer animal model, which is indicated PrLZ expression contributed to the malignancy progression of prostate cancer. In addition, PrLZ also might up regulate androgen receptor (AR) expression and increase the PSA expression, a putative downstream target gene of AR, which indicated PrLZ mediated the malignancy progression of prostate cancer was associated with androgen signals.
Mol Carcinog 2009 May
PMID:PrLZ expression is associated with the progression of prostate cancer LNCaP cells. 1880 Mar 46

Androgen receptor (AR) ligands are important for the development and function of several tissues and organs. However, the poor oral bioavailability, pharmacokinetic properties, and receptor cross-reactivity of testosterone, coupled with side effects, place limits on its clinical use. Selective AR modulators (SARMs) elicit anabolic effects in muscle and bone, sparing reproductive organs like the prostate. However, molecular mechanisms underlying the tissue selectivity remain ambiguous. We performed a variety of in vitro studies to compare and define the molecular mechanisms of an aryl propionamide SARM, S-22, as compared with dihydrotestosterone (DHT). Studies indicated that S-22 increased levator ani muscle weight but decreased the size of prostate in rats. Analysis of the upstream intracellular signaling events indicated that S-22 and DHT mediated their actions through distinct pathways. Modulation of these pathways altered the recruitment of AR and its cofactors to the PSA enhancer in a ligand-dependent fashion. In addition, S-22 induced Xenopus laevis oocyte maturation and rapid phosphorylation of several kinases, through pathways distinct from steroids. These studies reveal novel differences in the molecular mechanisms by which S-22, a nonsteroidal SARM, and DHT mediate their pharmacological effects.
Mol Endocrinol 2008 Nov
PMID:Steroidal androgens and nonsteroidal, tissue-selective androgen receptor modulator, S-22, regulate androgen receptor function through distinct genomic and nongenomic signaling pathways. 1880 30

Androgen receptor (AR) is a ligand-dependent transcription factor and its activity is regulated by numerous AR coregulators. Aberrant expression of AR coregulators in prostate cancer cells has an important role in the development and progression of prostate cancer. We report here that CDC25A, a cell cycle-promoting phosphatase over-expressed in a number of cancers, functions as an AR coregulator suppressing the AR transcriptional activity. In this study, we found that CDC25A is upregulated in human prostate cancer and its expression level is positively associated with the Gleason score and disease metastasis. More importantly, we showed that CDC25A can physically interact with AR through its putative catalytic domain. In addition, ectopic expression of CDC25A in prostate cancer cell lines suppresses PSA and Probasin promoter activities significantly, indicating that CDC25A may function as an AR corepressor. This was further confirmed by knockdown of endogenous CDC25A expression using small interfering RNA (siRNA), which resulted in upregulation of PSA promoter activity. Moreover, a truncated mutant that does not interact with AR fails to suppress the PSA promoter activity, indicating that CDC25A downregulates androgen-responsive promoter by physically interacting with AR. Taken together, our results demonstrated a novel function of CDC25A in the regulation of androgen signaling in human prostate cancer cells.
J Mol Biol 2009 Jan 16
PMID:CDC25A functions as a novel Ar corepressor in prostate cancer cells. 1901 80

The exon 1 of the human androgen receptor (AR) gene contains two length polymorphisms of CAG (polyglutamine) and GGN (polyglycine). "In vitro" experiments suggest that the larger GGN repeats provide a lower AR-protein yield, whereas the larger CAG repeats decrease the AR transcriptional activity, both decreasing the AR signalling intensity. Here we have tested such possibilities in human prostatic cancer (CaP) specimens. We used 72 archival samples of radical prostatectomy. Parallel slides were used for AR protein or PSA immunohistochemistry, and for genotyping studies. Polymorphisms were genotyped by PCR, fragment length analysis and sequencing selected samples. The AR staining was positively correlated with the Gleason score (r=0.320; P=0.005), but it was not correlated to CAG or GGN repeat length or PSA staining. The number of GGN repeats was negatively correlated to the intensity of PSA staining (r=-0.243; P=0.04). Combination of short alleles of both tracts was significantly higher in: the heavier stained tertiles for PSA (P=0.03) and AR (P=0.06); and in the subgroup of samples having a Gleason score of 7 or higher (P=0.021). The results support the hypothesis that the shorter alleles of CAG and GGN repeats in the AR gene are associated to an increased AR signalling intensity in human prostate cancer, and with more aggressive forms of the disease.
J Steroid Biochem Mol Biol 2009 Jan
PMID:Short alleles of both GGN and CAG repeats at the exon-1 of the androgen receptor gene are associated to increased PSA staining and a higher Gleason score in human prostatic cancer. 1909 61

Steroid hormones and their metabolising enzymes have been studied extensively for their potential role in prostate cancer, with more recent interest in the androgen/estrogen inactivating enzyme 17beta-hydroxysteroid dehydrogenase type 4 (HSD17B4). Gene expression profiling showed HSD17B4 to be significantly overexpressed in prostate cancer compared to matched-benign epithelium. We therefore hypothesized that altered HSD17B4 expression may contribute to prostate cancer progression via altered hormone balance. In this study, HSD17B4 mRNA and protein expression were assessed by in situ hybridisation (ISH) and immunohistochemistry (IHC), respectively, in tissue arrays of prostate tissue from 172 patients treated by radical prostatectomy. Overexpression of HSD17B4 mRNA and protein was associated with prostate cancer (P<0.0001) and multivariate Cox proportional hazards analysis, adjusted for known prognostic indicators, demonstrated HSD17B4 mRNA and high protein expression were significant independent predictors of poor patient outcome as measured by time until PSA relapse (mRNA: hazards ratio [HR]=1.90, 95% confidence interval [CI]=1.15-3.12; P<0.0001; and protein: HR=2.09, 95% CI=1.31-3.33; P=0.0026). Here we provide strong evidence that both mRNA and protein overexpression of HSD17B4 is not only associated with the presence of prostate cancer, but is also a significant independent predictor of poor patient outcome.
Mol Cell Endocrinol 2009 Mar 25
PMID:HSD17B4 overexpression, an independent biomarker of poor patient outcome in prostate cancer. 1910 Mar 8

Kallikrein 4 (KLK4) is a member of the human KLK gene family of serine proteases, many of which are implicated in hormone-dependent cancers. Like other KLKs, such as KLK3/PSA and KLK2, KLK4 gene expression is also regulated by steroid hormones in hormone-dependent cancers, although the transcriptional mechanisms are ill defined. Here, we have investigated the mechanisms mediating the hormonal regulation of KLK4 in breast (T47D) and prostate (LNCaP and 22Rv1) cancer cells. We have shown that KLK4 is only expressed in breast and prostate cancers that express the progesterone receptor (PR) and androgen receptor (AR), respectively. Expression analysis in PR- and AR-positive cells showed that the two predominant KLK4 variants that use either TIS1 or TIS2a/b are both up-regulated by progesterone in T47D cells and androgens in LNCaP cells. Two putative hormone response elements, K4.pPRE and K4.pARE at -2419 bp and -1005 bp, respectively, were identified in silico. Electrophoretic mobility shift assays and luciferase reporter experiments suggest that neither K4.pARE nor approximately 2.8 kb of the KLK4 promoter interacts directly with the AR to mediate KLK4 expression in LNCaP and 22Rv1 cells. However, we have shown that K4.pPRE interacts directly with the PR to up-regulate KLK4 gene expression in T47D cells. Further, chromatin immunoprecipitation experiments showed a time-dependent recruitment of the PR to the KLK4 promoter (-2496 to -2283), which harbors K4.pPRE. This is the first study to show that progesterone-regulated KLK4 expression in T47D cells is mediated partly by a hormone response element (K4.pPRE) at -2419 bp.
Mol Cancer Res 2009 Jan
PMID:Direct progesterone receptor and indirect androgen receptor interactions with the kallikrein-related peptidase 4 gene promoter in breast and prostate cancer. 1914 44


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