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)

Androgens mediate their effects through an intracellular receptor that is a member of the steroid/thyroid hormone family of receptors. The expression of this protein is tightly regulated in different tissues and among cell types within a single tissue. To define the mechanisms controlling the expression of the androgen receptor, we have isolated and characterized the promoter of the androgen receptor gene in the human prostate cell line LNCaP. The major site of transcription initiation is approximately 1.1 kilobases upstream of the initiator methionine of the androgen receptor protein. The promoter region lacks typical "TATA" and "CAAT" sequence motifs but lies in a GC-rich region and contains a putative Sp1 binding site characteristic of a "housekeeping" promoter and a 44-base segment composed of alternating adenosine and guanosine residues. S1 nuclease protection analyses indicate that the same promoter is employed both in human tissues (prostate, testes), in genital skin fibroblasts, in T47D and MCF-7 breast cancer cells, and in LNCaP prostate cancer cells.
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PMID:Expression of the human androgen receptor gene utilizes a common promoter in diverse human tissues and cell lines. 238 Jan 87

In order to measure beta1-SP1-glycoprotein (SP1), on RIA system by the 2-antibody method was established as a measuring method of the low concentration range. SP1 concentrations were measured by this method in the sera of women in early pregnancy, in the amniotic fluids of late pregnancy, in the sera of malignant tumour patients. Furthermore, SP1 concentrations in the sera of women in early pregnancy as well as E2, E3, progesterone and HCG concentrations in the same samples were measured, and correlations between them were examined. 1) The minimum sensitivity of this measuring system was 3ng/ml. The optimum concentration of samples was between 10 approximately 660ng/ml. 2) The correlation between the data obtained by this RIA method and the SRID method was as close as r = 0.9287. 3) SP1 concentrations in the sera of women in early pregnancy were 0.17 +/- 0.12 microgram/ml in the fifth week of pregnancy, showing an almost straight increase during the course of pregnancy, and were 31.62 +/- 3.20 microgram/ml in the 13th week of pregnancy. 4) SP1 concentrations in amniotic fluids were 1.09 approximately 2.20 microgram/ml and were equal to about 1% of SP1 concentrations in the sera of women in late pregnancy. SP1 concentrations in the sera of umbilical cord blood were 0.13 approximately microgram/ml, which were equal to about 0.1% of SP1 concentrations in the sera of women in late pregnancy. 5) SP1 was detected in all four samples of the choriocarcinoma patients' sera, and the concentrations were 25 approximately 2,600ng/ml. Sp1 was detected in 6 of the 15 samples of the cervical carcinoma patients' sera, and the detection rate was 40%. SP1 was detected in 3 of the 6 samples of the leukemia patients' sera and 1 of the 4 samples of the prostatic cancer patients' sera. SP1 detection rates and concentrations appeared to increase in the sera of cervical carcinoma and leukemia patients in accordance with the progress of the diseases. SP1 concentrations in the sera of women in early pregnancy were not correlative to measured E2 and E3 concentrations in the same samples, but there was a significant correlation with progesterone and HCG concentrations. The RIA method for measuring SP1, which we have established, is available for measuring SP1 in the low concentration range. The method is expected to be applied clinically, such as in examinations in early pregnancy, and will be available in fundamental studies such as attempts to measure the SP1 movement in malignant tumour patients, in cooperation with studies of the meaning of SP1 production at pregnancy.
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PMID:[Studies for a sensitive radioimmunoassay of beta1-Sp1-glycoprotein (SP1) (author's transl)]. 697 Jan 46

As a specific competitive inhibitor of 5alpha-reductase, an intracellular enzyme that converts testosterone to dihydrotestosterone, finasteride is being extensively used for the treatment of benign prostatic hyperplasia and in experimental settings for prostate cancer. In this study, we showed that finasteride markedly inhibited prostate-specific antigen (PSA) secretion and expression. The promoter of the PSA gene contains several well-known cis-regulatory elements. Among them, steroid receptor-binding consensus (SRBC) has been identified as a functional androgen-responsive element. Our previous study showed that PSA was not only present in conditioned medium of the PSA-positive LNCaP cells but was also detectable in small amounts in PSA-negative cell lines, PC-3 and DU-145 (L. G. Wang et al., Oncol. Rep., 3: 911-917, 1996). A strong correlation between binding of nuclear factors to SRBC and the level of PSA present in the conditioned medium and cell extracts was found in these three cell lines, whereas no such correlation with binding was obtained using Sp1 oligonucleotide as a probe. Binding of LNCaP cell nuclear proteins to SRBC was diminished when the cells were exposed to 25 microM finasteride, at which concentration 50% of both PSA mRNA and protein were inhibited. As a major component of DNA-protein complexes, the level of androgen receptor was dramatically decreased in the cells treated with finasteride. Our data indicate that inhibition of complex formation between SRBC and nuclear proteins due to the remarkable decrease in the level of androgen receptor plays a key role in the down-regulation of PSA gene expression by finasteride in LNCaP cells.
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PMID:Down-regulation of prostate-specific antigen expression by finasteride through inhibition of complex formation between androgen receptor and steroid receptor-binding consensus in the promoter of the PSA gene in LNCaP cells. 904 50

Decreased expression of the human KAI1 metastasis-suppressor gene is involved in the progression of human prostatic cancer and possibly lung and breast cancer. To evaluate the frequency of mutation and allelic loss during the progression of human cancer, as well as to determine the regulatory mechanism for the expression of the KAI1 gene in normal and cancerous tissues, we characterized the 5'-promoter region, exon/intron organization, and transcription initiation site of the human KAI1 gene. About 80 kb of DNA was identified as the human KAI1 gene, which contains 8 kb of 5'-region, 10 exons, 9 introns, and 8 kb of DNA following exon 10. The coding region starts in exon 3 and ends in exon 10. The size of intron 1 is 29 kb, which almost equals the sizes of all other introns combined. A CpG island is present in the 5'-promoter region and extends to exon 1 and intron 1. The promoter region has no TATA or CCAAT box but has many putative binding motifs for various transcription factors, including nine Sp1 sites and five AP2 sites. These results suggest a diverse regulatory mechanism for the expression of the KAI1 gene in human tissues. The transcription initiation site of the KAI1 gene is located 181 bp upstream of the first nucleotide of the translation initiation codon. Comparisons of gene structures between KAI1 and seven other members of the transmembrane 4 superfamily revealed that the splicing sites relative to the different structural domains of the predicted proteins are well conserved, suggesting that these genes are evolutionarily related and that they arose through gene duplication and divergent evolution.
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PMID:Genomic organization of the human KAI1 metastasis-suppressor gene. 912 78

FGF-1 mRNA is expressed in the prostate cancer cell lines LNCaP and PC-3 and in the breast carcinoma cell line MDA-MB-231. Levels of FGF-1 mRNA have been shown to be up-regulated by serum, phorbol esters, and combinations of growth factors. It was shown that the major FGF-1 mRNA species expressed following serum stimulation in MDA-MB-231 cells is FGF-1.C. To better understand the potential role of FGF-1 in human prostate and breast cancer, we began an analysis of the cis- and trans-acting elements of one of its promoters required for the serum, PMA, and androgen regulation in breast and prostate cancer cell lines. We show that FGF-1.C steady-state mRNA levels are increased following serum or PMA stimulation of PC-3 cells. Further, we determine the FGF-1.C transcription start site in PC-3 cells. By sequence analysis, we show that consensus AP1, AP2, and Sp1 sites and ARE- and CRE-near consensus elements are present in the immediate 5' region of the FGF-1.C transcription start site. Gel-shift assays show that oligonucleotides containing FGF-1.C AP1, AP2, or Spl sequences form specific DNA-protein complexes with nuclear extracts from PC-3 cells. To determine if these or other cis-acting sequences are responsible for the serum, androgen, or growth factor regulation of FGF-1 expression, fragments of the FGF-1.C promoter region were cloned upstream of the luciferase reporter gene. We show that FGF-1 synergizes with androgen to enhance FGF-1.C transcription in LNCaP cells. We further show that the DNA fragment containing sequence up to 1614 nucleotides upstream of the FGF-1.C transcription start site is sufficient for stimulating promoter activity following serum treatment of MDA-MB-231 cells. Thus, FGF-1.C promoter contains sequences that are important for androgen or serum stimulation in prostate and breast cancer cells.
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PMID:Regulation of a promoter of the fibroblast growth factor 1 gene in prostate and breast cancer cells. 971 43

Prostate cancer is the most common malignancy in males and is the second most common cause of cancer mortality in American men. Polymorphisms have been identified in two genes, the 17-hydroxylase cytochrome P450 gene (CYP17) and the steroid 5-reductase type II gene (SRD5A2) that are involved with androgen biosynthesis and metabolism. The CYP17 A2 allele contains a T-->C transition in the 5' promoter region that creates an additional Sp1-type (CCACC box) promoter site. The SRD5A2 valine to leucine (V89L) polymorphism has been correlated with lower dihydroxytestosterone levels. We tested genotypes in 108 prostate cases and 167 controls along with samples (n = 340) from several different ethnic groups. The CYP17 A2 allele (combined A1/A2 and A2/A2 genotypes) occurred at a higher frequency in Caucasian patients with prostate cancer (70%) than in Caucasian clinical control urology patients (57%), suggesting that the A2 allele may convey increased risk for prostate cancer [odds ratio (OR) = 1.7, 95% confidence interval (CI) = 1.0-3.0]. Blacks and Caucasians had a similar frequency of the A2 genotype (16 and 17%, respectively) while Taiwanese had the highest frequency (27%). The SRD5A2 leucine genotype was most frequent in Taiwanese (28%), intermediate in Caucasians (8.5%) and lowest in Blacks (2.5%). Genotypes having a SRD5A2 leucine allele were somewhat more common in prostate cancer cases (56%) than in controls (49%) (OR = 1.4, 95% CI = 0.8-2.2) but this difference was not significant. These results support the hypothesis that some allelic variants of genes involved in androgen biosynthesis and metabolism may be associated with prostate cancer risk.
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PMID:Prostate cancer risk and polymorphism in 17 hydroxylase (CYP17) and steroid reductase (SRD5A2). 1046 17

Human prostate-specific transglutaminase (hTG(P)) is a cross-linking enzyme encoded by the TGM4 gene. The TGM4 gene promoter was characterized by deletion mapping and mutational analysis. Promoter constructs, containing the minimal promoter requirements, could efficiently drive transcription in the prostate cancer cell lines PC346C and LNCaP and the hepatic cancer cell line Hep3B. The region between positions -113 and -61 was demonstrated to be essential for core promoter activity. Further analysis revealed the functional importance of an Sp1 binding motif, 5'-ACCCCGCCCC-3', at positions -96 to -87. This sequence is a binding site of the ubiquitous transcription factors Sp1 and Sp3.
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PMID:An Sp1 binding site is essential for basal activity of the human prostate-specific transglutaminase gene (TGM4) promoter. 1058 Jan 45

The discovery of a second estrogen receptor (ER), ERbeta, has led to a complete change in our views on estrogen action. The previous dogmatic view that ERalpha represented the only estrogen receptor led to a static and simplistic concept of mechanisms of estrogen action with conceptual limitations in the development of novel estrogenic and antiestrogenic drugs. It is now realized that estrogen signaling represents a complex and multi facetted signal transduction pathway with, at least in many cases, quite different roles of ERalpha and ERbeta. For instance, the two receptors appear to behave quite differently on AP1, antioxidant and Sp1-response elements where ERbeta mediates positive regulation by antiestrogens whereas ERalpha is silent under these conditions. ERalpha and ERbeta also appear to be differentially distributed in the body and within tissues. They are regulated differently and seem to have distinct biological roles, at least in certain contexts. Data are currently rapidly generated with respect to these issues from knockout animals with either of the two receptors deleted. Also double knockouts have been generated and apparently survive. ERbeta may well have significant roles in the etiology of the following diseases and symptoms: prostate cancer, osteoporosis, depression, as well as urinary incontinence in postmenopausal women. Attempts are ongoing in several labs to develop specific ligands to the two receptors. Such ligands may well turn out to be extremely important in treating the mentioned diseases and symptoms as well as possibly others.
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PMID:An update on estrogen receptors. 1070 63

Androgens via their cognate receptor may be involved in the development and progression of prostate cancer. The aim of this study was to determine whether tea polyphenols have inhibitory effects on androgen action in an androgen-responsive, prostate cancer cell line, LNCaP. The tea polyphenol, EGCG, inhibited LNCaP cell growth and the expression of androgen regulated PSA and hK2 genes. Moreover, EGCG had a significant inhibitory effect on the androgenic inducibility of the PSA promoter. Immunoblotting detected a decrease in androgen receptor protein with treatments of the tea polyphenols EGCG, GCG and theaflavins. Northern blot analysis showed decreased levels of androgen receptor mRNA by EGCG. Transient transfections demonstrated that EGCG and theaflavins could repress the transcriptional activities of the androgen receptor promoter region. An Sp1 binding site in the androgen receptor gene promoter is an important regulatory component for its expression. This study suggests Sp1 is the target for the tea polyphenols because treatments of EGCG decreased the expression, DNA binding activity and transactivation activity of Sp1 protein. In conclusion, we have described a new property of tea polyphenols that inhibits androgen action by repressing the transcription of the androgen receptor gene.
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PMID:Tea polyphenols down-regulate the expression of the androgen receptor in LNCaP prostate cancer cells. 1077 82

Loss of the CD44 transmembrane glycoprotein in primary prostate cancer has been shown to be associated with unfavorable clinical behavior. Moreover, the majority of prostate cancer metastases lack expression of this molecule. The mechanism of CD44 silencing in prostate cancer was investigated using both patient material and in vivo-propagated human prostate cancer xenografts. In 9 of 11 lymph node metastases of prostate cancer, we demonstrated by methylation-sensitive restriction enzyme digestion that the promoter region of the CD44 gene is methylated, indicating that this represents a major mechanism of CD44 silencing. Similarly, in 6 out of 12 in vivo-growing human prostate carcinoma xenograft models, hypermethylation of the CD44 gene was found. The extent of CpG island methylation was investigated by nucleotide sequencing after bisulphite modification of the CD44 promoter region. In the xenografts displaying hypermethylation, the examined 14 CpG sites in the CD44 transcription regulatory domain, including a Sp1 binding site, were consistently methylated. This correlated with reduced CD44 expression or lack of CD44 expression at mRNA and protein levels. In the xenografts lacking hypermethylation of the CD44 gene, high levels of CD44 mRNA and protein were expressed in some models, whereas in others CD44 mRNA expression was only detectable by RT-PCR and the CD44 protein could hardly be detected or was not detected at all. The results indicate that, in most prostate cancers, loss of CD44 expression is associated with extensive hypermethylation of the CpG island of the CD44 promoter region, but other, posttranscriptional mechanisms may also lead to CD44 loss.
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PMID:Silencing of CD44 expression in prostate cancer by hypermethylation of the CD44 promoter region. 1095 Jan 20


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