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)

Prostate specific membrane antigen (PSMA) is a 110 kDa type II transmembrane protein that is expressed exclusively by prostate tumor cells and as such is a clear cellular target in the development of a new method for fast and reliable diagnosis of prostate cancer. PSMA is highly homologous to the neuropeptidase NAALADase, and it has been shown that inhibitors of NAALADase also strongly bind to PSMA. In an effort to better understand the structural basis of the inhibitory activity of more than 60NAALADase inhibitors synthesized and tested by our group, we used Monte Carlo calculations employing the Merck Molecular Force Field to explore the conformational space available to a set of PSMA inhibitors. Conformational analysis indicated that the lower the number of unique conformations accessible by an inhibitor, the greater the biological activity displayed by the compound against LnCAP cells. This suggests that the difference in activity is largely entropy based. The key conformations associated with high activity are used to develop a simple pharmacophore model that led to the design of new, conformationally restricted analogues with potentially high activity in rational drug design.
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PMID:Conformational and SAR analysis of NAALADase and PSMA inhibitors. 1312 82

Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed at high levels in prostate cancer and in tumor-associated neovasculature. In this study, we report that PSMA is internalized via a clathrin-dependent endocytic mechanism and that internalization of PSMA is mediated by the five N-terminal amino acids (MWNLL) present in its cytoplasmic tail. Deletion of the cytoplasmic tail abolished PSMA internalization. Mutagenesis of N-terminal amino acid residues at position 2, 3, or 4 to alanine did not affect internalization of PSMA, whereas mutation of amino acid residues 1 or 5 to alanine strongly inhibited internalization. Using a chimeric protein composed of Tac antigen, the alpha-chain of interleukin 2-receptor, fused to the first five amino acids of PSMA (Tac-MWNLL), we found that this sequence is sufficient for PSMA internalization. In addition, inclusion of additional alanines into the MWNLL sequence either in the Tac chimera or the full-length PSMA strongly inhibited internalization. From these results, we suggest that a novel MXXXL motif in the cytoplasmic tail mediates PSMA internalization. We also show that dominant negative micro2 of the adaptor protein (AP)-2 complex strongly inhibits the internalization of PSMA, indicating that AP-2 is involved in the internalization of PSMA mediated by the MXXXL motif.
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PMID:A novel cytoplasmic tail MXXXL motif mediates the internalization of prostate-specific membrane antigen. 1452 23

The development of T-cell-based immunotherapies of cancer largely depends on the availability of tumour-associated antigens capable of eliciting tumour-directed cytotoxic T-cell responses. In prostate cancer, the number of antigens defined as suitable targets of cytotoxic T lymphocytes (CTLs) is still limited. Recently, prostein was identified as a transmembrane protein that is highly restricted to prostate tissues. In our study, prostein transcripts were found to be abundant in both malignant and nonmalignant prostate tissue samples. To identify immunogenic CD8+ T-cell epitopes, human leucocyte antigen-A(*)0201-binding peptides were selected from the amino-acid sequence of prostein and were used for the in vitro stimulation of CD8+ T lymphocytes. Specific CTLs were raised against the prostein-derived peptide CLAAGITYV that were capable of lysing prostate cancer cells, indicating that this peptide is naturally generated by tumour cells. Our data suggest that prostein is a suitable candidate to be included in a T-cell-based immunotherapy of prostate cancer.
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PMID:Identification of an HLA-A*0201-restricted T-cell epitope derived from the prostate cancer-associated protein prostein. 1499 4

Efforts are increasing to identify and evaluate diagnostic and therapeutic markers for prostate cancer patients. One of these, prostate-specific membrane antigen (PSMA), a transmembrane protein highly expressed in all types of prostatic tissue (eg, benign epithelium, benign prostatic hyperplasia, prostatic intra-epithelial neoplasia and adenocarcinomas, with increased binding affinity for malignant cells), is becoming an increasingly important diagnostic and therapeutic marker, not only for prostate cancer, but possibly for other malignant lesions. Recent studies have demonstrated PSMA expression in endothelial cells of tumor-associated neovasculature (including carcinoma of the colon, breast, bladder, pancreas, kidney and melanoma), thus greatly expanding its possible beneficial role, especially as new anti-PSMA mAbs continue to be developed and refined. Future diagnostic and therapeutic interventions utilizing these antibodies will become increasingly important in not only prostate cancer but perhaps many other different malignancy types.
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PMID:Monoclonal antibodies and prostate-specific membrane antigen. 1524 49

TMEM16A, TMEM16B, TMEM16C, TMEM16D, TMEM16E, TMEM16F and TP53I5 are TMEM16 family eight-transmembrane proteins with N- and C-terminal tails facing the cytoplasm. TMEM16A gene at human chromosome 11q13.3 is amplified in head and neck tumors, and TMEM16E gene at human chromosome 11p14.3 is mutated in gnathodiaphyseal dysplasia (GDD). Ngep cDNA (NM_207031.1) is derived from mouse Tmem16g gene. Here, we characterized human TMEM16G gene by using bioinformatics. TMEM16G gene, consisting of 25 exons, was located at human chromosome 2q37.3. Intra-species comparative genomics revealed that the PASK-PPP1R7-TMEM16G-HDLBP-NEDD5 locus was the unique region without paralogous region. TMEM16G mRNA was preferentially expressed in normal prostate and prostate cancer. Complete coding sequence of TMEM16G cDNA was determined by assembling 25 exons of TMEM16G gene. Human TMEM16G gene was found to encode 932-amino-acid TMEM16G protein with TM16H1, TM16H2 and TM16H3 domains. Comparative proteomics revealed that T844N amino-acid substitution occurred in human TMEM16G during evolution. TMHMM2 program predicted that mouse Tmem16g and artificial human TMEM16G (844T) were eight-transmembrane proteins, but that wild-type human TMEM16G (844N) was a seven-transmembrane protein. These facts indicate that amino-acid substitution at codon 844 of human TMEM16G resulted in the mis-folding of the eighth transmembrane helix. Human TMEM16G with altered membrane topology might show functional divergence compared with other members of the TMEM16 family.
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PMID:Characterization of human TMEM16G gene in silico. 1537 14

Lipid-modified soluble proteins Hedgehog (SHH, DHH and IHH) and WNT (WNT1, WNT2, WNT2B, WNT3, etc.) share distantly related mechanisms for ligand modification as well as for signaling through seven-transmembrane protein with Frizzled domain. Hedgehog and WNT signaling pathways network together during embryogenesis and carcinogenesis. Dispatched 1 (DISP1) and Dispatched 2 (DISP2) are human homologs for Drosophila Dispatched implicated in the release of lipid-anchored Hedgehog from producing cells. Here, we identified and characterized Dispatched 3 (DISP3) gene by using bioinformatics. DISP3 complete coding sequence was determined by assembling BU170953 EST and KIAA1337 uncharacterized cDNA. DISP3 gene at human chromosome 1p36.22 was linked to D1S2667 microsatellite maker and TERE1 gene, whose locus is associated with prostate cancer, bladder cancer, and liver cancer. DISP3 mRNA was expressed in human embryonic stem (ES) cells, brain, testis, lung carcinoid, neuroblastoma, retinoblastoma and brain tumor. DISPH1 domain with five transmembrane regions (codon 452-637 of DISP3) and DISPH2 domain with four transmembrane regions (codon 1116-1319 of DISP3) were identified as novel domains conserved between DISP3 (1392 aa) and DISP1. The region around DISPH1 and DISPH2 domains of DISP3 protein was the Patched homologous region conserved among Patched family members and DISP family members. Because DISP3 and DISP1 are multi-span transmembrane proteins with the Patched homologous region, DISP3 is predicted to be implicated in the release of lipid-anchored secreted proteins. This is the first report on identification and characterization of the DISP3 gene.
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PMID:Identification and characterization of DISP3 gene in silico. 1564 43

Radiotherapy is an effective approach for the treatment of local prostate cancer. However, once prostate cancer metastasizes, radiotherapy cannot be used due to the distribution of multiple metastases to lymph nodes and bones. In contrast, radioimmunotherapy should still be efficacious in metastatic prostate cancer as radioisotopes are brought to tumor cells by targeting antibodies. Here we identify and validate a prostate-expressed molecule, tomoregulin, as a target for radioimmunotherapy of prostate cancer. Tomoregulin is a transmembrane protein selectively expressed in the brain, prostate, and prostate cancer, but not expressed in other normal tissues. Immunohistochemical studies of tomoregulin protein in clinical samples show its location in the luminal epithelium of normal prostate, benign prostatic hyperplasia, and prostatic intraepithelial neoplasia. More importantly, the tomoregulin protein is expressed in primary prostate tumors and in their lymph node and bone metastases. The nature of tomoregulin as a transmembrane protein and its tissue-specific expression make tomoregulin an attractive target for radioimmunotherapy, in which tomoregulin-specific antibodies will deliver a radioisotope to prostate tumor cells and metastases. Indeed, biodistribution studies using a prostate tumor xenograft model showed that the (111)In-labeled anti-tomoregulin antibody 2H8 specifically recognizes tomoregulin protein in vivo, leading to a strong tumor-specific accumulation of the antibody. In efficacy studies, a single i.p. dose of 150 microCi (163 microg) (90)Y-labeled 2H8 substantially inhibits the growth rate of established LNCaP human prostate tumor xenograft in nude mice but produces no overt toxicity despite cross-reactivity of 2H8 with mouse tomoregulin. Our data clearly validate tomoregulin as a target for radioimmunotherapy of prostate cancer.
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PMID:Targeting tomoregulin for radioimmunotherapy of prostate cancer. 1580 86

We have identified a novel gene, six transmembrane protein of prostate 2 (STAMP2), named for its high sequence similarity to the recently identified STAMP1 gene. STAMP2 displays a tissue-restricted expression with highest expression levels in placenta, lung, heart, and prostate and is predicted to code for a 459-amino acid six transmembrane protein. Using a form of STAMP2 labeled with green flourescent protein (GFP) in quantitative time-lapse and immunofluorescence confocal microscopy, we show that STAMP2 is primarily localized to the Golgi complex, trans-Golgi network, and the plasma membrane. STAMP2 also localizes to vesicular-tubular structures in the cytosol and colocalizes with the Early Endosome Antigen1 (EEA1) suggesting that it may be involved in the secretory/endocytic pathways. STAMP2 expression is exquisitely androgen regulated in the androgen-sensitive, androgen receptor-positive prostate cancer cell line LNCaP, but not in androgen receptor-negative prostate cancer cell lines PC-3 and DU145. Analysis of STAMP2 expression in matched normal and tumor samples microdissected from prostate cancer specimens indicates that STAMP2 is overexpressed in prostate cancer cells compared with normal prostate epithelial cells. Furthermore, ectopic expression of STAMP2 in prostate cancer cells significantly increases cell growth and colony formation suggesting that STAMP2 may have a role in cell proliferation. Taken together, these data suggest that STAMP2 may contribute to the normal biology of the prostate cell, as well as prostate cancer progression.
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PMID:Molecular cloning and characterization of STAMP2, an androgen-regulated six transmembrane protein that is overexpressed in prostate cancer. 1589 94

Prostate-specific membrane antigen (PSMA) is a relatively omnipresent, but unique Type II dimeric transmembrane protein with a multiplicity of functions and has been shown to be a reasonable target for immunological approaches such as vaccines or more directed therapy with radioactively labelled monoclonal antibodies against PSMA. Given the abundance of various glycoprotein and carbohydrate antigens expressed on the surface of prostate cancer cells and cell lines, PSMA stands out as another 'self' antigen which is not only expressed on cancer cells, but on neovasculature. Although vaccines are varied in their design and target goal, recent technology has afforded researchers the opportunity to induce recruitment of multiple effector cell populations, cytokines and factors which can elicit both cellular and humoral responses. This review serves to present unique approaches in vaccine development which can induce immunological responsiveness with potential impact on disease progression and to introduce PSMA as a potential target for multimodality therapies.
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PMID:Targeting novel antigens for prostate cancer treatment: focus on prostate-specific membrane antigen. 1594 73

The transmembrane protein TMEFF2, also known as tomoregulin or TENB2, has been proposed as a potential immunotherapeutic target for the treatment of prostate cancer. Much attention has focused on its limited tissue distribution, with strong expression seen only in the brain and the prostate. Here we describe the identification of a novel splice variant of TMEFF2 expressed both in the normal prostate and in prostate cancer. This variant encodes an isoform of TMEFF2 that is truncated after the first four coding exons, eliminating both the EGF-like and the transmembrane domains. Fusion of GFP to this isoform demonstrated that this variant transcript produces a truncated TMEFF2 protein (TMEFF2-S). In contrast to full-length TMEFF2-GFP, the truncated TMEFF2-S-GFP fusion protein was enriched in cytosolic granules, showed no staining at the plasma membrane, and was secreted into the medium of transfected cells grown in tissue culture. These results indicate that a truncated isoform of TMEFF2 is expressed from this locus. This secreted form of TMEFF2 may functionally interact with full-length TMEFF2, or its binding partners, and may also influence current immune-based treatment strategies.
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PMID:A truncated isoform of TMEFF2 encodes a secreted protein in prostate cancer cells. 1643 95


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