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)

There is evidence that predisposition to cancer has a genetic component. Genetic models have suggested that there is at least one highly penetrant gene predisposing to this disease. The oncogene MXI1 on chromosome band 10q24-25 is mutated in a proportion of prostate tumours and loss of heterozygosity occurs at this site, suggesting the location of a tumour suppressor in this region. To investigate the possibility that MXI1 may be involved in inherited susceptibility to prostate cancer, we have sequenced the HLH and ZIP regions of the gene in 38 families with either three cases of prostate cancer or two affected siblings both diagnosed below the age of 67 years. These are the areas within which mutations have been described in some sporadic prostate cancers. No mutations were found in these two important coding regions and we therefore conclude that MXI1 does not make a major contribution to prostate cancer susceptibility.
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PMID:No germline mutations in the dimerization domain of MXI1 in prostate cancer clusters. The CRC/BPG UK Familial Prostate Cancer Study Collaborators. Cancer Research Campaign/British Prostate Group. 937 79

Two human divalent cation transporters of the ZIP family, hZip1 and hZip2, homologous to Irt1 (Arabidopsis thaliana), the first identified member, have been described. They were shown by transfection into K562 cells to be localized at the plasma membrane and to mediate zinc uptake. Here we report a differential subcellular localization of hZip1 according to cell type. By transient expressions of EGFP-hZip1, FLAG-tagged or native hZip1, we observed that hZip1 has a vesicular localization in COS-7 cells or in several epithelial cell lines, corresponding partially to the endoplasmic reticulum. Using anti-hZip1 antibodies, we confirmed the intracellular localization of the endogenous protein in PC-3, a prostate cancer cell line.
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PMID:Differential subcellular localization of hZip1 in adherent and non-adherent cells. 1169 49

The CCAAT/enhancer binding protein alpha (C/EBPalpha) protein is essential for proper lung and liver function and granulocytic and adipose tissue differentation. It was hypothesized that abnormalties in C/EBPalpha function contribute to the development of malignancies in a variety of tissues. To test this, genomic DNA from 408 patient samples and 5 cell lines representing 11 different cancers was screened for mutations in the C/EBPalpha gene. Two silent polymorphisms termed P1 and P2 were present at frequencies of 13.5% and 2.2%, respectively. Of the 12 mutations detected in 10 patients, silent changes were identified in one nonsmall cell lung cancer, one prostate cancer, and one acute myelogenous leukemia (AML) subtype M4. The 9 remaining mutations were detected in 1 of 92 (1.1%) myelodysplastic syndrome (MDS) samples and 6 of 78 (7.7%) AML (AML-M2 and AML-M4) samples. Some mutations truncated the predicted protein with loss of the DNA-binding (basic region) and dimerization (leucine zipper [ZIP]) domains by either deletions or nonsense codons. Also, inframe deletions or insertions in the fork region located between the leucine zipper and basic region, or within the leucine zipper, disrupted the alpha-helical phase of the bZIP domain. The inframe deletion and insertion mutations abrogated the transcriptional activation function of C/EBPalpha on the granulocyte colony-stimulating factor receptor promoter. These mutants localized properly to the nucleus, but were unable to bind to the C/EBP site in the promoter and did not possess dominant-negative activity. The mutations in the MDS patient and one AML-M2 patient were biallelic, indicating a loss of C/EBPalpha function. These results suggest that mutation of C/EBPalpha is involved in specific subtypes of AML and in MDS, but may occur rarely in other types of leukemias or nonhematologic malignancies.
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PMID:Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. 1183 Apr 84

BACKGROUND: As part of a long-term initiative to improve cancer surveillance in New York State, small area maps of relative risk, expressed as standardized incidence ratios (SIRs), were produced for the most common cancers. This includes prostate cancer, the focus of this paper, since it is the most common non-dermatologic malignancy diagnosed among men and the second leading cause of cancer deaths for men in the United States.ZIP codes were chosen as mapping units for several reasons, including the need to balance between protecting personal privacy and public demand for fine geographic resolution. Since the population size varies greatly among such small mapping units, hierarchical Bayes spatial modelling was applied in this paper to produce a map of smoothed SIRs. It is further demonstrated how other characteristics of the large sample from the stationary posterior distribution of SIRs can be mapped to investigate various aspects of the statewide spatial pattern of prostate cancer incidence. RESULTS: Thematic mapping of the median and 95 percentile range of SIRs provided, respectively, a map of spatially smoothed values and the uncertainty associated with these smoothed values. Maps were also produced to identify ZIP codes expressing a 95% probability, in the Bayesian paradigm, of being less than or greater than the null value of 1. CONCLUSION: The model behaved as expected since areas that were statistically elevated coincided with areas identified by the spatial scan statistic, plus the relative uncertainty increased as a ZIP code's population decreased, with an exaggerated effect for low population ZIP codes on the edge of the state border.The overall smoothed pattern, along with identified high and low areas, may reflect difference across the state with respect to socio-demographics and risk factors; however, this is confounded by potential differences in screening and diagnostic follow-up. Nevertheless, the Bayes modelling approach is shown to provide not only smoothed results, but also considerable other information from a large empirical distribution of outcomes associated with each mapping unit.
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PMID:Small area mapping of prostate cancer incidence in New York State (USA) using fully Bayesian hierarchical modelling. 1558 79

Monte Carlo methods are commonly used to assess the statistical significance of disease clusters. This usually involves permuting the observed outcome measure, such as the rate of disease, across the geographic units within the study area. When the variance of the disease rates is heterogeneous, however, randomizing the disease rate across the geographic units results in over-estimating the p-values in areas of low variance and under-estimating the p-values in areas of high variance. This bias results in under-ascertainment of clusters in urban areas and over-ascertainment of clusters in rural areas. As an alternative, randomizing the number of cases of disease or deaths proportional to the population at risk preserves the variance structure of the study area, therefore resulting in unbiased statistical inference. We compare results from randomizing rates with those from randomizing case counts, using county-level prostate cancer mortality data for the United States and ZIP-Code level prostate cancer incidence data for New York State, using the local Moran's I statistic.
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PMID:Effects of randomization methods on statistical inference in disease cluster detection. 1640 44

Par-4 (prostate apoptosis response 4) is a pro-apoptotic protein and tumour suppressor that was originally identified as a gene product up-regulated during apoptosis in prostate cancer cells. Here, we show, for the first time, that Par-4 is expressed and co-localizes with the actin filament bundles in vascular smooth muscle. Furthermore, we demonstrate that targeting of ZIPK to the actin filaments, as observed upon PGF-2alpha stimulation, is inhibited by the presence of a cell permeant Par-4 decoy peptide. The same decoy peptide also significantly inhibits PGF-2alpha induced contractions of smooth muscle tissue. Moreover, knockdown of Par-4 using antisense morpholino nucleotides results in significantly reduced contractility, and myosin light chain and myosin phosphatase target subunit phosphorylation. These results indicate that Par-4 facilitates contraction by targeting ZIPK to the vicinity of its substrates, myosin light chain and MYPT, which are located on the actin filaments. These results identify Par-4 as a novel regulator of myosin light chain phosphorylation in differentiated, contractile vascular smooth muscle.
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PMID:The pro-apoptotic protein Par-4 facilitates vascular contractility by cytoskeletal targeting of ZIPK. 1850 70

Prostate apoptosis response-4 (Par-4) was initially identified as a gene product up-regulated in prostate cancer cells undergoing apoptosis. In rat fibroblasts, coexpression of Par-4 and its interaction partner DAP-like kinase (Dlk, which is also known as zipper-interacting protein kinase [ZIPK]) induces relocation of the kinase from the nucleus to the actin filament system, followed by extensive myosin light chain (MLC) phosphorylation and induction of apoptosis. Our analyses show that the synergistic proapoptotic effect of Dlk/Par-4 complexes is abrogated when either Dlk/Par-4 interaction or Dlk kinase activity is impaired. In vitro phosphorylation assays employing Dlk and Par-4 phosphorylation mutants carrying alanine substitutions for residues S154, T155, S220, or S249, respectively, identified T155 as the major Par-4 phosphorylation site of Dlk. Coexpression experiments in REF52.2 cells revealed that phosphorylation of Par-4 at T155 by Dlk was essential for apoptosis induction in vivo. In the presence of the Par-4 T155A mutant Dlk was partially recruited to actin filaments but resided mainly in the nucleus. Consequently, apoptosis was not induced in Dlk/Par-4 T155A-expressing cells. In vivo phosphorylation of Par-4 at T155 was demonstrated with a phospho-specific Par-4 antibody. Our results demonstrate that Dlk-mediated phosphorylation of Par-4 at T155 is a crucial event in Dlk/Par-4-induced apoptosis.
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PMID:Par-4 is an essential downstream target of DAP-like kinase (Dlk) in Dlk/Par-4-mediated apoptosis. 1962 47

Zinc(II) ions contribute to a number of biological processes e.g. DNA synthesis, gene expression, enzymatic catalysis, neurotransmission, and apoptosis. Zinc(II) dysregulation, deficiency and over-supply are connected with various diseases, particularly cancer. 98 % of human body zinc(II) is localized in the intracellular compartment, where zinc(II) is bound with low affinity to metallothionein (MT). Zinc transporters ZIP and ZnT maintain transmembrane transport from/to cells or organelles. Imbalance of their regulation is described in cancers, particularly prostate (down-regulated zinc transporters ZIP1, 2, 3 and ZnT-2) and breast, notably its high-risk variant (up-regulated ZIP6, 7, 10). As a result, intracellular and even blood plasma zinc(II) levels are altered. MT protects cells against oxidative stress, because it cooperates with reduced glutathione (GSH). Recent studies indicate elevated serum level of MT in a number of malignancies, among others in breast, and prostate. MT together with zinc(II) affect apoptosis and proliferation, thus together with its antioxidative effects it may affect cancer. To date, only little is known about the influence of zinc(II) and MT on cancer, while these compounds may play an important role in pathogenesis. This review concludes current data regarding the impact of zinc(II) on the pathogenesis of breast and prostate cancers with potential outlines of new, targeted therapy and prevention. Moreover, blood plasma zinc(II) and MT levels and dietary zinc(II) intake are discussed in relation to breast and prostate cancer risk.
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PMID:Insight to physiology and pathology of zinc(II) ions and their actions in breast and prostate carcinoma. 2205 Jul 52

This paper presents a geostatistical approach to combine two geographical sets of area-based data into the mapping of disease risk, with an application to the rate of prostate cancer late-stage diagnosis in North Florida. This methodology is used to combine individual-level data assigned to census tracts for confidentiality reasons with individual-level data that were allocated to ZIP codes because of incomplete geocoding. This form of binomial kriging, which accounts for the population size and shape of each geographical unit, can generate choropleth or isopleth risk maps that are all coherent through spatial aggregation. Incorporation of both types of areal data reduces the loss of information associated with incomplete geocoding, leading to maps of risk estimates that are globally less smooth and with smaller prediction error variance.
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PMID:Geostatistical analysis of health data with different levels of spatial aggregation. 2246 93

The activation of AKT governs many signaling pathways and promotes cell growth and inhibits apoptosis in human malignancies including prostate cancer (CaP). Here, we investigated the molecular association between AKT activation and the function of death-associated protein kinase 3 (DAPK3) in CaP. An inverse correlation of pAKT and DAPK3 expression was seen in a panel of CaP cell lines. Inhibition of AKT by wortmannin/LY294002 or overexpression of DAPK3 reverts the proliferative function of AKT in CaP cells. On the other hand, ectopic expression of AKT inhibited DAPK3 function and induced proliferation of CaP cells. In addition, AKT over-expressed tumors exhibit aggressive growth when compared to control vector in xenograft models. The immunohistochemistry results revealed a down-regulation of DAPK3 expression in AKT over-expressed tumors as compared to control tumors. Finally, we examined the expression pattern of AKT and DAPK3 in human CaP specimens - the expected gradual increase and nuclear localization of pAKT was seen in higher Gleason score samples versus benign hyperplasia (BPH). On the contrary, reduced expression of DAPK3 was seen in higher Gleason stages versus BPH. This suggests that inhibition of DAPK3 may be a contributing factor to the carcinogenesis of the prostate. Understanding the mechanism by which AKT negatively regulates DAPK3 function may suggest whether DAPK3 can be a therapeutic target for CaP.
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PMID:Activation of AKT negatively regulates the pro-apoptotic function of death-associated protein kinase 3 (DAPK3) in prostate cancer. 2712 62


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