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)

Kallikreins are a subgroup of serine proteases with diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis. By using molecular cloning techniques, we identified a new human kallikrein gene, tentatively named KLK15 (for kallikrein 15 gene). This new gene maps to chromosome 19q13.4 and is located between the KLK1 and KLK3 genes. KLK15 is formed of five coding exons and four introns, and shows structural similarity to other kallikreins and kallikrein-like genes. KLK15 has three alternatively spliced forms and is primarily expressed in the thyroid gland and to a lower extent in the prostate, salivary, and adrenal glands and in the colon testis and kidney. Our preliminary results indicate that the expression of KLK15 is up-regulated by steroid hormones in the LNCaP prostate cancer cell line. The KLK15 gene is also up-regulated, at the mRNA level, in prostate cancer in comparison to normal prostatic tissue. KLK15 up-regulation was found to be associated with more aggressive forms of prostate cancer. This newly discovered gene has the potential of being used as a diagnostic and/or prognostic marker for prostate cancer.
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PMID:Molecular cloning of the human kallikrein 15 gene (KLK15). Up-regulation in prostate cancer. 1101 Sep 66

A novel gene, designated UROC28, was identified by an agarose gel-based differential display technique, and it was found to be up-regulated in prostate, breast, and bladder cancer. Expression of UROC28 was also up-regulated in prostate cancer cells in the presence of androgens as demonstrated by relative quantitative reverse transcription-PCR. The elevated expression of this gene was observed to increase in surgically removed tissues concomitantly with rising Gleason grade and was most elevated in metastatic tissue. UROC28 protein was detected in serum by Western slot blot analyses, and a significant higher UROC28 protein level was found in sera of prostate cancer individuals compared with normal individuals and individuals with nonmalignant prostatic hyperplasia. Northern analyses in normal tissues showed that the UROC28 cDNA hybridizes to two mRNAs at about 2.1 and 2.5 kb. Nucleic acid sequence analyses indicated that these two alternatively spliced mRNA variants differ only at the 3' untranslated region. These two mRNAs encode the same protein with 135 amino acids. Bioinformation analyses suggest that there is a possible transmembrane domain from amino acid aa34 to aa50, three protein kinase-C phosphorylation sites at aa62 (SQK), aa89 (TMK), and aa94 (SMK), and one myristylation site at aa118 (GLECCL). Genomic Southern hybridization and chromosomal mapping demonstrated that UROC28 is encoded by a single copy of gene at chromosome 6q23-24. In situ hybridization and immunohistochemistry experiments further confirmed up-regulation of this gene in prostate and breast cancers with the expression localizing to the glandular epithelium. This gene did not demonstrate increased expression in lung and colon cancer tissues.
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PMID:Cloning and characterization of UROC28, a novel gene overexpressed in prostate, breast, and bladder cancers. 1115 5

There is ample evidence that deregulation of apoptosis results in the development, progression, and/or maintenance of cancer. Since many apoptotic regulatory genes (e.g. bcl-x) code for alternatively spliced protein variants with opposing functions, the manipulation of alternative splicing presents a unique way of regulating the apoptotic response. Here we have targeted oligonucleotides antisense to the 5'-splice site of bcl-x(L), an anti-apoptotic gene that is overexpressed in various cancers, and shifted the splicing pattern of Bcl-x pre-mRNA from Bcl-x(L) to Bcl-x(S), a pro-apoptotic splice variant. This approach induced significant apoptosis in PC-3 prostate cancer cells. In contrast, the same oligonucleotide treatment elicited a much weaker apoptotic response in MCF-7 breast cancer cells. Moreover, although the shift in Bcl-x pre-mRNA splicing inhibited colony formation in both cell lines, this effect was much less pronounced in MCF-7 cells. These differences in responses to oligonucleotide treatment were analyzed in the context of expression of Bcl-x(L), Bcl-x(S), and Bcl-2 proteins. The results indicate that despite the presence of Bcl-x pre-mRNA in a number of cell types, the effects of modification of its splicing by antisense oligonucleotides vary depending on the expression profile of the treated cells.
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PMID:Modification of alternative splicing of Bcl-x pre-mRNA in prostate and breast cancer cells. analysis of apoptosis and cell death. 1127 82

Inheritance of mutations in the breast cancer susceptibility gene, BRCA2, predisposes humans to breast and ovarian cancers. Inherited mutations in the BRCA2 gene are also known to cause susceptibility to prostate cancer. BRCA2 protein exists in a large multi-protein complex from which a novel structural DNA binding protein BRCA2-associated factor 35 (BRAF35) has been isolated. We have cloned a novel cDNA encoding an alternatively spliced protein of BRAF35, designated as BRAF25. BRAF25 transcript is present in various human cells. We have precisely mapped the BRAF25 cDNA sequence to the genomic chromosome 19 sequence. Analysis of the predicted sequence of BRAF25 identified a protein of 215 amino acids. BRAF25 contains a truncated high mobility group domain, a kinesin-like coiled-coil domain and multiple Src homology 2 (SH2) motifs. Western blot analysis using antibodies specific for BRAF25 revealed the presence of BRAF25 in human prostate cancer cells.
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PMID:Cloning a cDNA encoding an alternatively spliced protein of BRCA2-associated factor 35. 1208 79

BRAF25 is an alternatively spliced protein of BRAF35 (see associated paper). We have mapped the BRAF25 gene to chromosome sub-band 19p13.3, a region where loss of chromosomal heterozygosity has been reported in about 50% of ovarian cancers. Because of the high incidence of genetic links of prostate cancer to breast and ovarian cancers, we investigated the BRAF25 expression in the prostate specimens. Immunohistochemical analysis using antibodies specific for BRAF25 revealed a strong immunostaining in sections of the benign prostatic hyperplasia (BPH). The staining was concentrated on the nuclei of cells facing the lumen of prostatic glands, even though the sporadic nuclei of cells in stromas were also stained. However, the expression of BRAF25 was dramatically reduced in intermediate prostate cancer and absent in advanced prostate cancer. Preincubation of the antibody with the immunizing peptide abolished immunostaining in BPH specimens. Therefore, the expression of BRAF25 was gradually lost in prostate cancer.
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PMID:Immunohistological detection of BRAF25 in human prostate tumor and cancer specimens. 1208 80

Loss of heterozygosity (LOH) at chromosome 13q14 is one of the most recurrent anomalies observed in sporadic prostate tumors. This LOH is believed to unmask recessive mutations that inactivate a tumor-suppressor gene(s) which otherwise regulates normal cell growth and suppresses abnormal cell proliferation. Identification of potential tumor-suppressor genes within the deleted region is a way of indicating putative pathways of prostate cancer development and progression. The main target that disappears or is downregulated as a result of 13q14 loss remains to be identified. Therefore, our first concern was to find a gene located in the 13q14 region whose transcription is reduced. CHC1-L, for chromosome condensation 1-like, is mapped to the smallest common deleted region. CHC1-L expression is significantly reduced in prostate tumors compared to normal prostate tissues (p = 0.0002). In 21 of 36 (58%) primary prostate tumors studied, CHC1-L expression was reduced at least 2-fold, as measured by real-time quantitative RT-PCR; 18 of the tumors (50%) showed 13q14 LOH for at least 1 of the 5 polymorphic markers that we studied in the region, and 14 (78%) of these were among the tumors underexpressing CHC1-L. CHC1-L is alternatively spliced at its 5' end to produce 2 isoforms, of 551 and 526 aa. Analyses of CHC1-L integrity and of the quantitative expression of its variants indicate that the observed underexpression in prostate tumors is related to reduced expression of the 551 aa isoform. Although CHC1-L is not the obvious candidate given its only known homology, to RCC1, a guanine nucleotide exchange factor for the Ras-related GTPase Ran, the frequent significant decrease observed in its expression in prostate cancer associated with the difference in frequency of CHC1-L variant isoforms between normal and neoplastic prostate tissues places it in a pivotal role or possibly adjacent to a gene that has that role in prostate cancer evolution.
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PMID:CHC1-L, a candidate gene for prostate carcinogenesis at 13q14.2, is frequently affected by loss of heterozygosity and underexpressed in human prostate cancer. 1211 2

RT-nested PCR has been introduced as a highly specific and sensitive assay method to detect the prostate-specific membrane antigen (PSM) mRNA in peripheral blood. However, appreciable percentages of false-positive cases have been reported. Additionally, primer sets reported previously could not discriminate between PSM and PSM', an alternatively spliced variant, mRNA. These isoforms can be produced from a single gene. Switches in alternative splicing patterns are often controlled with strict cell-type or developmental-stage specificity. Therefore, it is most important to discriminate between PSM mRNA and PSM' mRNA. Using our highly specific primer sets, PSM mRNA was detected in 3 of 24 peripheral blood samples of normal male volunteers (12.5%) and was not detected in peripheral blood of 11 normal female volunteers. PSM' mRNA was detected in 5 of 24 peripheral blood samples of normal male volunteers (20.8%) and in 4 of 11 of normal female volunteers (36.4%). PSM' mRNA induced false-positive results, it is important for genetic diagnosis of prostate cancer to discriminate between PSM and PSM' using our primer sets with high specificity. The advances in the uniquely designed primer sets may allow researchers to detect a real PSM mRNA without PSM' mRNA.
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PMID:Detection of circulating prostate tumor cells: alternative spliced variant of PSM induced false-positive result. 1237 3

Due to the characteristics of the luteal phase of the ovarian cycle in the dog, which spans a prolonged time period, this species is a suitable model to study the role of progestins in both normal morphogenic and abnormal tumorigenic processes in the mammary gland. It has been convincingly shown that progestins, including endogenous progesterone, induce the synthesis of growth hormone (GH) in the normal and the tumorous canine mammary gland. The growth hormone receptor (GHR) is also expressed in normal and tumorous canine mammary tissues and in this concise overview we highlight recent advances in our understanding of the significance of the GH/GHR system for mammary gland (patho)biology. In an attempt to unravel the cellular and molecular mechanisms associated with the GH/GHR system, we were able to show that both GH and GHR are differentially expressed in normal canine mammary tissues. Maximum expression of both GH and GHR occurs during the proliferation phase of the tissue, which links the progestin-induced mammary GH synthesis to the progestin-associated proliferation of epithelial cells in the mammary gland. Expression of the GH/GHR system is also present in most canine mammary tumors, albeit that GHR expression may be downregulated in undifferentiated mammary carcinomas. Upon GH stimulation of the GHR-positive CMT-U335 canine mammary tumor cell line, the transcription factors STAT5A and STAT5B become phosphorylated on their tyrosine residues, which is likely to reflect the significance of mammary GH in vivo. Molecular analysis of the canine mammary GHR transcripts by RT-PCR provided evidence for normal and alternative processing of the GHR primary transcript encoding the full-length plasma membrane GHR and at least four putative GH binding proteins (GHBPs), respectively. The translation products from the alternatively spliced GHR transcripts indicate an intact N-terminal ligand binding domain and an unique C-terminal portion, lacking the transmembrane domain and cytoplasmic tail. Thus, these proteins are considered to be able to bind GH, but have lost their signaling potential. The exact biological role of these GHBPs remains to be established, but GHBPs may have a transport function in the endocrine route, regulate the level of biologically available GH locally, or dominant-negatively influence the full-length plasma membrane GHR. In dog mammary cancer specimens strongly reduced levels of alternatively spliced GHR transcripts were found compared to the non-malignant mammary tissue. Notably, expression of both GH and GHR in mammary cancer cells is not restricted to dogs. Recent experiments generated evidence for GH and GHR expression in human breast cancer cells, and also in human prostate cancer cells, which represents another highly prevalent hormone-sensitive human malignancy. In agreement with our findings in the dog, the expression of the hGH-N gene in human mammary cancer cells seemed to correlate positively with their progesterone receptor status, which warrants, in our opinion, a reconsideration of the role of progestins in breast cancer of women. In human prostate cancer cells four different hGH-N transcripts were detected, which encode classical 22 kDa GH and GH-related proteins. Consistent with the findings on the canine GHR, different GHR transcripts in human mammary cancer cells and prostate cancer cells were detected encoding the full-length plasma membrane GHR and putative GHBPs.
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PMID:Morphogenic and tumorigenic potentials of the mammary growth hormone/growth hormone receptor system. 1243 8

Testis specific protein (TSPY) is a human Y-chromosome derived gene with numerous functional and non-functional copies. Specific expression patterns in testis and testicular tumors, as in prostate cancer samples and cell lines led to the postulation of a potential role in cell proliferation, supported by the presence of a suppressor of variegation, enhancer of zeste and Trithorax/nucleosome assembling protein (nucleosome assembly protein) domain in the mature protein. Expression studies have now identified two transcripts of variable length, termed TSPY-S and -L, which differ in their 3'-translated region due to alternative splicing, and in the quantitative level of transcripts, with TSPY-S being at least 3-4-fold more abundant. In immunoblot experiments on human testis and LNCaP protein extracts using an anti-peptide-antiserum against the TSPY-L specific C-terminus TSPY-L was characterized as a functional variant on the protein level. As there are at least three intragenic positions differing between various TSPY genes and thus defining certain haplotypes, the alternatively spliced TSPY transcripts were analysed for their haplotypes in order to link them to well defined TSPY loci. Surprisingly, no evidence of a G-G-18 haplotype was found for the TSPY-L transcript, while this haplotype makes up almost 50% of all TSPY-S transcripts. This excludes the corresponding TSPY-1 locus from alternative splicing. The only significant differences between the TSPY-1 locus and eight other loci were identified in the promotor region as revealed by detailed sequence comparisons. Thus one might speculate that the alternative splicing could be influenced by elements binding to the promotor region.
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PMID:Expression, alternative splicing and haplotype analysis of transcribed testis specific protein (TSPY) genes. 1252 92

We report the primary characterization of a new gene KCNRG mapped at chromosome band 13q14.3. This gene includes three exons and has two alternatively spliced isoforms that are expressed in normal tissues and in some tumor cell lines. Protein KCNRG has high homology to tetramerization domain of voltage-gated K+ channels. Using the patch-clamp technique we determined that KCNRG suppresses K+ channel activity in human prostate cell line LNCaP. It is known that selective blockers of K+ channels suppress lymphocyte and LNCaP cell line proliferation. We suggest that KCNRG is a candidate for a B-cell chronic lymphocytic leukemia and prostate cancer tumor suppressor gene.
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PMID:A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3. 1265 Sep 44


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