bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuregulin promotes autophagic cell death of prostate cancer cells
Authors: Tal‐Or Pazit , Di‐Segni Ayelet , Lupowitz Zipora , Pinkas‐Kramarski Ronit 
Published: March 2003

AbstractBackgroundProstate cancer is one of the most frequently diagnosed cancers in males. Autocrine/paracrine growth factors for the epidermal growth factor receptor (EGFR) have been identified in prostate tumors suggesting a role for EGFR in the progression of prostate cancer. The androgen‐dependent prostate cancer cell line, LNCaP, expresses the EGFR as well as two additional members of the family; ErbB‐2 and ErbB‐3, which can be activated by neuregulin (NRG) isoforms. The effect of ErbB ligands on the viability of LNCaP cells was studied.MethodsIn the present study, we examined the effect of NRG on LNCaP cell growth and survival in the absence of androgen mimetic by the MTT assay, FACS analysis, nuclei staining, and Western blotting.ResultsOur results demonstrate that NRG activates ErbB‐2/ErbB‐3 heterodimers and induces cell death of LNCaP cells. By contrast, EGF activates ErbB‐1/ErbB‐1 or ErbB‐1/ErbB‐2 dimers and induces cell growth and survival. Interestingly, LNCaP cells treated with PI3K inhibitor underwent cell death but cells treated with both NRG and PI3K inhibitor survived as the control cells, indicating that the PI3K pathway may mediate NRG‐induced cell death. NRG‐induced cell death was not inhibited by the broad‐spectrum caspases inhibitor, benzyloxycarbonyl‐Val‐Ala‐Asp‐fluoromethylketone (Z‐VAD‐FMK). However, NRG‐induced cell death was inhibited by type II cell death inhibitor, 3‐methyladenine.ConclusionsThese results suggest that NRG induces type II cell death of LNCaP cells through PI3K‐dependent pathway. Prostate 55: 147–157, 2003. © 2003 Wiley‐Liss, Inc.
Expression‐patterns of the RNA component (hTR)and the catalytic subunit (hTERT) of human telomerase in nonneoplastic prostate tissue, prostatic intraepithelial neoplasia, and prostate cancer
Authors: Bettendorf Olaf , Heine Bernhard , Kneif Sören , Eltze Elke , Semjonow Axel , Herbst Hermann , Stein Harald , Böcker Werner , Poremba Christopher 
Published: March 2003

AbstractBackgroundTelomerase, a ribonucleoprotein, is composed of a RNA component (hTR) and two protein subunits. One of these subunits, the catalytic subunit (human telomerase reverse transcriptase, hTERT), represents a reverse transcriptase. hTERT‐expression is closely correlated with telomerase activity. The telomerase is thought to be involved in immortalization process. By adding hexamic repeats to the end of chromosomal DNA, the telomeres, the enzyme is able to stop progresssive telomeric DNA loss that occurs during cell division due to the end replication problem that stops the mitotic clock.MethodsExpression‐patterns of hTR using radioactive in situ hybridization with 35S‐labelled RNA probes were compared with immunhistochemical staining for hTERT in 14 cases of archival paraffin‐embedded samples of normal prostatic tissue, high‐grade prostatic intraepithelial neoplasia (PIN), prostatic cancer, and one atypical adenomatous hyperplasia (AAH). Beside the expression‐patterns each telomerase component was evaluated semiquantitatively.ResultshTERT and hTR can be found in nonneoplstic tissue and are upregulated in premalignant transformated lesions. AAH showed no hTERT‐expression and low hTR‐expression. There is a heterogenous expression within prostatic carcinomas.ConclusionsNo association was observed between the grade of the tumour differentiation and semiquantitative levels of hTR‐ or hTERT‐expression. Telomerase is of limited value for the diagnostic of malignant or benign lesions in prostate. Prostate 55: 99–104, 2003. © 2003 Wiley‐Liss, Inc.
KLF5 is frequently deleted and down‐regulated but rarely mutated in prostate cancer
Authors: Chen Ceshi , Bhalala Hina V. , Vessella Robert L. , Dong Jin‐Tang 
Published: March 2003

AbstractBackgroundsPrevious studies mapped a region at the q21 band of chromosome 13 (13q21), which is frequently deleted in various human cancers including prostate cancer, suggesting the existence of a tumor suppressor gene at 13q21. The target gene of deletion in prostate cancer, however, has not been identified at present.MethodsWe examined four non‐neoplastic and 18 neoplastic prostatic cell lines or xenografts. Homozygous/hemizygous deletion was detected by assays of duplex PCR and real‐time PCR. Expression levels of genes were determined by the methods of RT‐PCR, real time PCR, and northern blot analysis. Mutations of KLF5 were detected by the approaches of single strand conformational polymorphism (SSCP) and direct sequencing. For the detection of promoter methylation, Southern blotting of genomic DNA and restriction digestion or SSCP analysis of methylation specific PCR products were used. Finally, an expression plasmid of KLF5 was introduced into prostate cancer cell lines with reduced KLF5 expression to investigate colony formation for cell growth.ResultsA 2‐Mb region of homozygous deletion at 13q21 was detected in the LUCaP70 xenograft of prostate cancer. This region of deletion was further narrowed to 142 Kb by a hemizygous deletion in the NCI‐H660 cell line. KLF5 was identified as the only complete gene in the smallest region of deletion. Quantitative deletion of KLF5 genome occurred in six of the 18 (33%) prostate cancer xenografts/cell lines. Each of the six samples with deletion also showed loss of expression for KLF5, suggesting that hemizygous deletion is one mechanism for loss of KLF5 expression. In total, 16 of the 18 cases (89%) showed loss of KLF5 expression at different degrees. In contrast, mutations and promoter methylations were not detected in any of the samples. Functionally, restoration of KLF5 in DU 145 and 22Rv1 cell lines significantly inhibited their growth in vitro.ConclusionsFrequent genomic deletion and loss of expression as well as cell growth suppression indicate that KLF5 is a reasonable candidate for the tumor suppressor gene at 13q21 in prostate cancer. Mutation and promoter methylation are not common mechanisms for the inactivation of KLF5 in prostate cancer. Prostate 55: 81–88, 2003. © 2003 Wiley‐Liss, Inc.
Expression of NKX3.1 in normal and malignant tissues
Authors: Gelmann Edward P. , Bowen Cai , Bubendorf Lukas 
Published: March 2003

AbstractBackgroundNKX3.1, a member of the NK‐class of homeodomain proteins, is expressed primarily in the adult prostate and has growth suppression and differentiating effects in prostate epithelial cells.MethodsWe performed immunohistochemical analysis for NKX3.1 and PSA expression in 4,061 samples included in a tissue microarray of a broad spectrum of human cancers and normal tissues.ResultsNKX3.1 expression was seen in prostate epithelial cells, prostate cancer, normal testis, 9% of primary and 5% of metastatic infiltrating ductal breast carcinoma, and 27% of primary and 26% of metastatic infiltrating lobular breast carcinoma. In a cohort of 474 primary breast cancers with median follow‐up over 62.5 month survival, we found no effect of NKX3.1 expression on prognosis. NKX3.1 expression was more restricted than the spectrum of prostate specific antigen expression.ConclusionsExpression of NKX3.1 is highly restricted and is found primarily in benign and malignant prostatic epithelial cells and also in normal testis and lobular carcinoma of the breast. Prostate 55: 111–117, 2003. © 2003 Wiley‐Liss, Inc.
Family history of prostate cancer and obesity in relation to high‐grade disease and extraprostatic extension in young men with prostate cancer
Authors: Rohrmann Sabine , Roberts William W. , Walsh Patrick C. , Platz Elizabeth A. 
Published: March 2003

AbstractBackgroundLittle is known about predictors of prostate cancer severity in young men. Therefore, we examined whether family history and obesity influence risk of high‐grade disease and extraprostatic extension in men < 55‐years old.MethodsFour hundred ninety‐eight men aged < 55 years who had had a radical prostatectomy (1992–1999) by one surgeon were mailed a survey in 2000 to assess family history of PCa and anthropometrics. Body mass index (BMI = kg/m2) was calculated as an indicator of obesity. Logistic regression was used to compute odds ratios (OR) for high‐grade disease (Gleason score ≥ 7) and extraprostatic extension.ResultsOf the 363 respondents, 35.8% had at least one first‐degree relative with PCa. Men with a family history were younger at surgery than those without a family history (48.8 vs. 50.1 years, P < 0.001). After controlling for age, cigarette smoking, and race/ethnicity, men with an affected father had a lower risk of high‐grade disease compared to those without an affected father (OR = 0.42, 95% CI 0.23–0.76). Risk of high‐grade disease increased with increasing BMI, especially in men < 50‐years old (P‐trend = 0.02). Family history and BMI were not clearly associated with extraprostatic extension.ConclusionsAfter taking into account a younger age at presentation among men with a family history, young men with a family history of PCa were less likely to have high‐grade disease. Obesity may be associated with a poorer histology in young men with PCa, especially in men younger than 50 years of age. Prostate 55: 140–146, 2003. © 2003 Wiley‐Liss, Inc.
Differential expression and/or activation of P38MAPK, erk1/2, and jnk during the initiation and progression of prostate cancer
Authors: Uzgare Aarti R. , Kaplan Paula J. , Greenberg Norman M. 
Published: March 2003

AbstractBackgroundMembers of the mitogen‐activated protein kinase (MAPK) family are capable of transducing signals from a wide variety of stimuli, including growth factors, G‐protein coupled receptors, and cytokines that are likely to play a role in the initiation and/or progression of prostate cancer.MethodsThe expression and activation of three members of the MAPK family, namely, erk, jnk, and p38MAPK was examined using Western blotting and immunohistochemistry during tumor progression in a transgenic mouse model for prostate cancer.ResultsActivation of p38MAPK was significantly elevated (2.3‐fold) in well‐differentiated prostatic tumors compared to normal controls. Furthermore, prostatic intraepithelial neoplastic (PIN) lesions expressing activated p38MAPK were observed to be proliferative rather than apoptotic. Expression of activated erk1/2 also preferentially co‐located to a sub‐population of epithelial cells within PIN lesions that correlated with Ki67 expression. In dramatic contrast, activated forms of erk1/2, jnk, and p38MAPK were reduced or absent in late stage adenocarcinomas and metastatic deposits.ConclusionsErk1/2, jnk, and p38MAPKs are differentially expressed and/or activated during prostate cancer progression. Activation of both erk1/2 and p38MAPK occurs concomitant with prostatic epithelial cell proliferation and the initiation of prostate cancer while inactivation is contemporaneous with the emergence of the poorly differentiated metastatic and androgen‐independent phenotype. Prostate 55: 128–139, 2003. © 2003 Wiley‐Liss, Inc.
Ca2+‐activated Cl− channel currents in rat ventral prostate epithelial cells
Authors: Kim Sung Joon , Shin Sun Young , Lee Ji Eun , Kim Jun Hee , Uhm Dae‐Yong 
Published: March 2003

AbstractBackgroundIn many epithelial tissues, the Cl− efflux via Ca2+‐activated Cl− channels (ClCa) play a key role for the fluid secretion. To elucidate the mechanism of prostatic fluid secretion, the properties of whole‐cell chloride conductance were investigated.Materials and MethodsRat prostate secretory epithelial cells (RPSECs) were isolated by collagenase treatment, and were used for the whole‐cell voltage clamp. Both extra‐ and intracellular monovalent cations were replaced by N‐methyl‐D‐glucamate to record the Cl− current selectively.ResultsA bath application of Ca2+‐ionophore, ionomycin (0.2 μM), increased the membrane conductance with outwardly rectifying voltage‐dependence. On step‐like depolarization from −60 to +80 mV (500 msec), the ionomycin‐induced current showed slowly activating kinetics, a known property of ClCa current (ICl(Ca)) of other tissues. The relative permeability of ClCa to various anions was calculated from the reversal potentials measured under a total replacement of extracellular Cl− with various anions, and the relative order of permeability was SCN−>I−>Br−>Cl−>>gluconate. The amplitude of ICl(Ca) was decreased by various anion channel blockers: niflumic acid (100 μM), DPC (100 μM), DIDS (1 mM), and NPPB (200 μM).ConclusionsRPSECs have ClCa that may provide Cl− efflux pathways for the exocrine secretions of the prostate. Prostate 55: 118–127, 2003. © 2003 Wiley‐Liss, Inc.
Negative bacterial polymerase chain reaction (PCR) findings in prostate tissue from patients with symptoms of chronic pelvic pain syndrome (CPPS) and localized prostate cancer
Authors: Leskinen Markku J. , Rantakokko‐Jalava Kaisu , Manninen Raija , Leppilahti Mikael , Marttila Timo , Kylmälä Timo , Tammela Teuvo L. J. 
Published: March 2003

AbstractBackgroundThe etiology of chronic pelvic pain syndrome (CPPS) remains obscure. Although, bacterial etiology has frequently been suggested, evidence of both bacterial involvement in CPPS and the presence of normal bacterial flora in the prostate remain uncertain.Materials and MethodsWe investigated the presence of bacterial DNA using polymerase chain reaction (PCR) techniques on prostatic tissue samples obtained in radical prostatectomy from 10 patients with moderate to severe symptoms of CPPS and 10 nonsymptomatic patients with localized prostate cancer. For symptom evaluation we used the National Institutes of Health‐Chronic Prostatitis Symptom Index (NIH‐CPSI).ResultsAll but one sample were negative for bacterial DNA. The PCR from a symptomatic patient was reproducibly positive in 16S rDNA PCR but negative in 23S rDNA PCR. Bacterial DNA was found in only one out of two sample aliquots and cloning yielded different sequences in two PCR products.ConclusionsA bacterial etiology for CPPS symptoms could not be demonstrated in patients with prostate cancer. The results also suggest that the prostate is unlikely to harbor bacterial normal flora. Prostate 55: 105–110, 2003. © 2003 Wiley‐Liss, Inc.
Registering α‐helices and β‐strands using backbone CH…O interactions
Authors: Singh S. Kumar , Babu M. Madan , Balaram P. 
Published: March 2003

AbstractThe possible occurrence of a novel helix terminating structural motif in proteins involving a stabilizing short CH…O interaction has been examined using a dataset of 634 non‐homologous protein structures (≤2.0 Å). The search for this motif was prompted by the crystallographic characterization of a novel structural feature in crystals of a synthetic decapeptide in which extension of a Schellman motif led to the formation of a CH…O hydrogen bond between the T‐4 CαH and the T+1 CO groups, where T is the helix terminator adopting a left handed (αL) conformation. More than 100 such motifs with backbone conformation superposing well with the peptide examples were identified. In several examples, formation of this motif led to an approximately antiparallel arrangement of a helical segment with an extended β‐strand. Careful examination of these examples suggested the possibility of registering antiparallel arrangement of helices and strands by means of backbone CH…O interactions with a regular periodicity. Model building resulted in the generation of idealized αβ and βα motifs, which can then be generalized to higher‐order repetitive structures. Inspection of the antiparallel αβ motif revealed a significant propensity for Ser, Glu, and Gln residues at the T‐4 position resulting in further stabilization using an O…HN side‐chain–backbone hydrogen bond. Modeling studies revealed ready accommodation of serine residues along the helix face that contacts the strand. The theoretically generated folds correspond to “open” polypeptide structures. Proteins 2003;51:167–171. © 2003 Wiley‐Liss, Inc.
Pharmacophore‐based molecular docking to account for ligand flexibility
Authors: Joseph‐McCarthy Diane , Thomas Bert E. , Belmarsh Michael , Moustakas Demetri , Alvarez Juan C. 
Published: March 2003

AbstractRapid computational mining of large 3D molecular databases is central to generating new drug leads. Accurate virtual screening of large 3D molecular databases requires consideration of the conformational flexibility of the ligand molecules. Ligand flexibility can be included without prohibitively increasing the search time by docking ensembles of precomputed conformers from a conformationally expanded database. A pharmacophore‐based docking method whereby conformers of the same or different molecules are overlaid by their largest 3D pharmacophore and simultaneously docked by partial matches to that pharmacophore is presented. The method is implemented in DOCK 4.0. Proteins 2003;51:172–188. © 2003 Wiley‐Liss, Inc.
Molecular dynamics simulations of a protein model in uniform and elongational flows
Authors: Lemak Alexandre S. , Lepock James R. , Chen Jeff Z. Y. 
Published: March 2003

AbstractWe present a molecular dynamics study of the conformational deformation of a minimalist β‐barrel protein model in two different types of hydrodynamic flows: uniform and elongational. We investigate the characteristics of protein stretching, paying special attention to the unfolding intermediate states and their relationship to the protein folding/unfolding problem. In the uniform flow simulations, one end of the modeled protein was tethered to a fixed point in space and the forced unfolding process was observed. The unfolding takes place via a few stages involving one or two intermediate states, depending on which end is tethered. The calculated force‐extension curves show plateau regimes and hysteresis as the protein is stretched and refolded, in qualitative agreement with the experimental measurements. The physical behavior observed in our numerical simulations of the forced unfolding in an elongational flow is very different from that in uniform flow. The protein unfolds abruptly from the globular state to a fully stretched state without going through any observable intermediate states. From these observation, we stress that protein unfolding pathways under the influence of an external force are highly dependent on the mechanism of the exerted force. Proteins 2003;51:224–235. © 2003 Wiley‐Liss, Inc.
Hierarchical protein folding pathways: A computational study of protein fragments
Authors: Haspel Nurit , Tsai Chung‐Jung , Wolfson Haim , Nussinov Ruth 
Published: March 2003

AbstractWe have previously presented a building block folding model. The model postulates that protein folding is a hierarchical top‐down process. The basic unit from which a fold is constructed, referred to as a hydrophobic folding unit, is the outcome of combinatorial assembly of a set of “building blocks.” Results obtained by the computational cutting procedure yield fragments that are in agreement with those obtained experimentally by limited proteolysis. Here we show that as expected, proteins from the same family give very similar building blocks. However, different proteins can also give building blocks that are similar in structure. In such cases the building blocks differ in sequence, stability, contacts with other building blocks, and in their 3D locations in the protein structure. This result, which we have repeatedly observed in many cases, leads us to conclude that while a building block is influenced by its environment, nevertheless, it can be viewed as a stand‐alone unit. For small‐sized building blocks existing in multiple conformations, interactions with sister building blocks in the protein will increase the population time of the native conformer. With this conclusion in hand, it is possible to develop an algorithm that predicts the building block assignment of a protein sequence whose structure is unknown. Toward this goal, we have created sequentially nonredundant databases of building block sequences. A protein sequence can be aligned against these, in order to be matched to a set of potential building blocks. Proteins 2003;51:203–215. © 2003 Wiley‐Liss, Inc.
Automated generation of MCSS‐derived pharmacophoric DOCK site points for searching multiconformation databases
Authors: Joseph‐McCarthy Diane , Alvarez Juan C. 
Published: March 2003

AbstractAll docking methods employ some sort of heuristic to orient the ligand molecules into the binding site of the target structure. An automated method, MCSS2SPTS, for generating chemically labeled site points for docking is presented. MCSS2SPTS employs the program Multiple Copy Simultaneous Search (MCSS) to determine target‐based theoretical pharmacophores. More specifically, chemically labeled site points are automatically extracted from selected low‐energy functional‐group minima and clustered together. These pharmacophoric site points can then be directly matched to the pharmacophoric features of database molecules with the use of either DOCK or PhDOCK to place the small molecules into the binding site. Several examples of the ability of MCSS2SPTS to reproduce the three‐dimensional pharmacophoric features of ligands from known ligand–protein complex structures are discussed. In addition, a site‐point set calculated for one human immunodeficiency virus 1 (HIV1) protease structure is used with PhDOCK to dock a set of HIV1 protease ligands; the docked poses are compared to the corresponding complex structures of the ligands. Finally, the use of an MCSS2SPTS‐derived site‐point set for acyl carrier protein synthase is compared to the use of atomic positions from a bound ligand as site points for a large‐scale DOCK search. In general, MCSS2SPTS‐generated site points focus the search on the more relevant areas and thereby allow for more effective sampling of the target site. Proteins 2003;51:189–202. © 2003 Wiley‐Liss, Inc.
Subunit E of mitochondrial ATP synthase: A bioinformatic analysis reveals a phosphopeptide binding motif supporting a multifunctional regulatory role and identifies a related human brain protein with the same motif
Authors: Hong Sangjin , Pedersen Peter L. 
Published: March 2003

AbstractThe mitochondrial adenosine triphosphate (ATP) synthase is located in the inner membrane and consists of at least 16 subunit types in animals, one of which is subunit e, the function of which is not clearly defined. A highly homologous protein is located in the nucleus and named progesterone receptor binding protein (RBF), to designate its role in this organelle. In addition, the expression level of subunit e in mammalian cells fluctuates greatly and is induced by certain carcinogens and elevated in liver cancers. Because these previous observations suggested to us that subunit e may play multifunctional regulatory roles, we employed a bioinformatic approach to test this view. First, from sequence alignment studies, secondary structure analyses, and basic local alignment search tool (BLAST) searches, we concluded that mitochondrial subunit e and the homologous nuclear protein RBF are most likely the same protein. Second, we examined the known sequence and structure of one of the most common multifunctional cell regulatory proteins, the 14‐3‐3 protein, involved in phosphopeptide binding, and deduced that it has an apparent binding motif (—KX6R––—RY—). Third, from careful examination of the conserved residues within all subunit e sequences in the database, we discovered that this protein has a comparable binding motif (—RY––—KX6R—). Finally, in a BLAST search for additional homologs of subunit e, we found a human brain protein, KIAA1578, the C‐terminal 30 amino acids of which are identical to those of human subunit e. This protein also contains a potential phosphopeptide binding motif. In summary, these studies provide support for the view that subunit e is a multifunctional cell regulator involved in cell signaling, and implicate the involvement of the KIAA1578 protein in cell signaling as well. These studies suggest also that, while functioning as a subunit of mitochondrial ATP synthases, subunit e may help regulate these complexes by binding to phosphopeptides within one or more of the other subunit types. Proteins 2003;51:155–161. © 2003 Wiley‐Liss, Inc.