Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-(4-Hydroxyphenyl)retinamide (4-HPR), a retinoic acid analog, induces apoptosis in several cell types. The mechanism by which 4-HPR initiates apoptosis remains poorly understood. We examined the effects of 4-HPR on two prostate carcinoma cell lines, LNCaP (an androgen-sensitive, p53(+/+) cell line) and PC-3 (an androgen-insensitive, p53(-/-) cell line). 4-HPR caused sustained c-Jun N-terminal kinase (JNK) activation and apoptosis in LNCaP cells but not in PC-3 cells at the dosages tested. Activation of JNK by 4-HPR was independent of caspases because a pan-caspase inhibitor failed to suppress JNK activation. Ultraviolet-C and gamma-radiation induced JNK activation in both LNCaP and PC-3 cells, suggesting that the failure of PC-3 cells to respond to 4-HPR was due to defects upstream of the JNK pathway. Furthermore, gamma-radiation-induced JNK activation was suppressed by an antioxidant, but 4-HPR-induced JNK activation was not, indicating that these two stimuli induced JNK activation through different mechanisms. Forced expression of JNK1, but not a JNK1 mutant, caused apoptosis in both LNCaP and PC-3 cells, suggesting that p53 is not required for JNK-mediated apoptosis. 4-HPR-induced apoptosis in LNCaP cells was suppressed by curcumin, which inhibits JNK activation. Expression of dominant-negative mutants in the JNK pathway also inhibited 4-HPR-induced apoptosis in human embryonic kidney 293 cells. Collectively, these results suggest that the JNK pathway mediates 4-HPR-induced apoptotic signaling.
Mol Pharmacol 1999 Dec
PMID:c-Jun N-terminal kinase mediates apoptotic signaling induced by N-(4-hydroxyphenyl)retinamide. 1057 55

mRNA differential display polymerase chain reaction analysis was used to screen systematically for novel androgen-regulated genes in the human prostatic adenocarcinoma cell line LNCaP. A 232 bp PCR fragment was found to be consistently down-regulated by the synthetic androgen R1881. Sequencing revealed complete identity with the human homologue of mouse Paternally expressed gene 3 (Peg3), an imprinted gene that plays an important role as a downstream mediator of the effects of tumor necrosis factor (TNF). The down-regulation of Peg3 mRNA by androgens was confirmed by Northern blot hybridization. The effect proved time and dose dependent with maximal repression (3.5-fold) after 24 h of treatment with 10(-8) M R1881. The steroid specificity of Peg3 mRNA regulation reflected the aberrant ligand specificity of the mutated androgen receptor in LNCaP cells, supporting the involvement of the androgen receptor in the repression process. Basal expression of Peg3 mRNA was almost completely abolished by the protein synthesis inhibitor cycloheximide. Experiments with Actinomycin D suggested that androgens act at a transcriptional level rather than by changing the stability of Peg3 mRNA. Comparison of the expression of Peg3 mRNA in 50 different human tissues revealed ubiquitous expression, but low levels in the prostate. The highest levels were observed in endocrine tissues such as ovary, placenta, adrenal and pituitary. High levels were also noted in various parts of the brain. No detectable levels of Peg3 mRNA were observed in two other androgen receptor-positive prostate tumor cell lines (MDA PCa-2a and -2b), and in the poorly differentiated and androgen receptor-negative prostate tumor lines PC-3 and DU-145. It is concluded that both androgens and loss of differentiation may affect the expression of Peg3, a mediator of the effects of TNF. Further experiments will be required to explore whether these changes affect the responsiveness of prostate tumor cells to TNF.
Mol Cell Endocrinol 1999 Sep 10
PMID:Androgens down-regulate the expression of the human homologue of paternally expressed gene-3 in the prostatic adenocarcinoma cell line LNCaP. 1058 Aug 40

In our cloning strategy to identify tyrosine kinases implicated in the regulation of prostate growth, the dog fer cDNA was obtained and shown to be highly homologous to known fer cDNAs. Using a polyclonal Fer antibody directed against a C-terminal peptide, we studied its associations with cortactin, beta-catenin and p120Cas in human prostate carcinoma PC-3 cells. In contrast to previous reports, no interactions were observed. To assess its functional role, fer cDNA constructs were transfected in PC-3 cells. Antisense clones exhibiting a marked diminution of Fer expression had a reduced growth rate (doubling time of 29 vs. 42 h) and were unable to form colonies in soft agar. In agreement with these results, Fer protein expression was linked to human prostatic proliferative diseases, with enhanced levels in extracts from cancer tissues as compared to those from normal and hyperplastic ones, and was also expressed in the human prostate carcinoma cell lines DU145 and LNCaP. In the dog model, Fer expression was up-regulated in dividing versus resting prostate epithelial cells in vitro, and also in vivo when basal cell hyperplasia and metaplasia was induced by estrogen after castration. Minimal effects were observed when renewing the luminal epithelium with androgens. Taken together, these results show that Fer expression is associated with prostate cell proliferation and enhanced in prostate cancer.
Mol Cell Endocrinol 2000 Jan 25
PMID:Links between Fer tyrosine kinase expression levels and prostate cell proliferation. 1068 53

We developed a new stable prostatic cell line expressing the human androgen receptor (AR) and the AR-responsive reporter gene to generate a powerful tool for investigating androgen action and for rapid screening of agonists and antagonists. The AR-deficient PC-3 cells were stably transfected with pSG(5)-puro-hAR and pMMTV-neo-Luc. After selection with puromycin and neomycin, one highly inducible clone was isolated and named PALM, for PC-3-Androgen receptor-Luciferase-MMTV. The expression of hAR was confirmed by western blot and steroid-binding assays on the whole cells. The transcriptional activity of the clone was measured after incubation of cells with increasing concentrations of synthetic R1881 or natural androgens (DHT and testosterone). The three agonists had the same maximal activity at 0.1 microM and the fold induction was equal to 20. The agonist and antagonist activities of the steroidal antiandrogens (cyproterone acetate and RU2956) and the non-steroidal antiandrogens (nilutamide, bicalutamide, inocoterone and hydroxyflutamide) measured with the PALM cells were in good correlation with the results obtained with transiently transfected cells. The selectivity in steroid transactivation was demonstrated with estradiol, progesterone, cortisol, dexamethasone and aldosterone. Spironolactone and RU486 showed partial agonist and antagonist activities, whereas R5020 presented only a partial antagonist activity. We here demonstrate that this stable transfectant provides an accurate tool for studying wild-type human AR activation and its regulation by androgens and antiandrogens in a human prostatic epithelial cell, which is routinely available and remains androgen-responsive in vitro.
Mol Cell Endocrinol 2000 Feb 25
PMID:A stable prostatic bioluminescent cell line to investigate androgen and antiandrogen effects. 1071 37

Prolactin stimulates citrate accumulation in prostate cells by increasing the expression of mitochondrial aspartate aminotransferase (mAAT). In this study, we further investigated the mechanism of prolactin regulation of mAAT expression in rat lateral prostate and LNCaP and PC-3 prostate cancer cells. Prolactin and 12-O-tetra-decanoylphorbol 13-acetate (TPA) increased the mAAT mRNA level twofold to fourfold. In addition, prolactin and TPA increased protein kinase C (PKC) activity in prostate cells 20% to 60% and 40% to 210%, respectively. The effects of both prolactin and TPA on mAAT mRNA were eliminated by downregulation of PKC. The effect of prolactin and TPA on gene transcription was determined using mAAT-chloramphenicol acetyltransferase (CAT) reporter-gene constructs, transiently transfected into PC-3 cells. The 59 untranslated region of the precursor form (pmAAT) of the mAAT gene contains five sequences that are homologous to the consensus TPA response elements (TRE). Reporter constructs with various combinations of these sequences were used to assay prolactin stimulation of CAT transcription in PC-3 cells. Prolactin increased CAT expression in PC-3 cells transfected with a reporter gene containing four of the TRE consensus sequences. Another CAT reporter gene, which contained two of the putative TREs, was also stimulated by prolactin, but a third reporter, containing the two other TRE sequences, was not induced by prolactin. These results suggest that prolactin regulates mAAT at the transcriptional level. Moreover, because both prolactin and TPA induced PKC activity, and because the effects of prolactin and TPA were eliminated when PKC was downregulated, we postulate that the prolactin effect on mAAT expression is mediated via the diacylglycerol PKC signal transduction pathway in rat lateral prostate and human prostate cancer cells.
Mol Urol 1999
PMID:Protein Kinase C Mediates Prolactin Regulation of Mitochondrial Aspartate Aminotransferase Gene Expression in Prostate Cells. 1085 Dec 92

Receptor protein tyrosine phosphatase alpha (RPTPalpha) is a transmembrane protein phosphatase, and has been proposed to be involved in the differentiation of the neuronal system. In the present study, we demonstrated the expression of RPTPalpha mRNA in several normal human tissues. We further investigated the regulation of expression of RPTPalpha mRNA in epithelial cells utilizing three commercially available human prostate cancer cell lines LNCaP, PC-3 and DU145. This is because these cells exhibit different levels of differentiation, defined by the expression of a tissue-specific differentiation antigen, prostatic acid phosphatase (PAcP), and their androgen sensitivity. LNCaP cells express PAcP and are androgen-sensitive cells, while PC-3 and DU145 cells do not express PAcP and are androgen-insensitive cells. Northern blot analyses revealed that, in LNCaP cells, fetal bovine serum (FBS) and 5alpha-dihydrotestosterone (DHT) down-regulates RPTPalpha mRNA expression, similar to the effect on PAcP. Contrarily, FBS up-regulated the RPTPalpha mRNA level in PC-3 and DU145 cells. In LNCaP cells, sodium butyrate inhibited cell growth and up-regulated RPTPalpha as well as PAcP mRNA expression. Although, sodium butyrate also inhibited the growth of PC-3 and DU145 cells, the level of RPTPalpha mRNA was decreased in PC-3, while increased in DU145 cells. Thus, data taken together indicate that the expression of RPTPalpha is apparently regulated by a similar mechanism to that of PAcP in LNCaP cells.
Mol Cell Biochem 2000 May
PMID:Expression of receptor protein tyrosine phosphatase alpha mRNA in human prostate cancer cell lines. 1093 23

Germline mutations of BRCA1 and BRCA2 predispose to hereditary breast, ovarian, and possibly prostate cancer, yet structural mutations in these genes are infrequent in sporadic cancer cases. To better define the involvement of these genes in sporadic cancers, we characterized expression levels of BRCA1 and BRCA2 transcripts in cancer cell lines derived from neoplasms of the ovary, prostate, and breast and compared them with those expressed in primary cultures of normal epithelial cells established from these organs. We observed upregulation of BRCA1 and/or BRCA2 expression in six of seven ovarian cancer cell lines (OVCA420, OVCA429, OVCA432, ALST, DOV13, and SKOV3) when compared with levels found in normal ovary surface epithelial cells. Furthermore, five cancerous or immortalized prostatic epithelial cell lines (BPH-1, TSU-Pr1, LNCaP, PC-3, and DU145) also expressed higher levels of BRCA1 and/or BRCA2 mRNA than did primary cultures of normal prostatic epithelial cells. In contrast, only the estrogen receptor-positive MCF-7 cell line overexpressed these messages, whereas the estrogen receptor-negative breast cancer cell lines Hs578T, MDA-MB-231, and MDA-MB-468 showed no change in expression levels when compared with normal breast epithelial cells. In addition, expanding on our recent identification of a novel BRCA2 transcript variant carrying an in-frame exon 12 deletion (BRCA2 delta 12), we report increased expression of this variant in several ovarian, prostate, and mammary cancer cell lines (OVCA420, OVCA433, ALST, DOV13, SKOV3, TSU-Pr1, DU145, and MDA-MB-468). Most notably, high levels of BRCA2 delta 12 mRNA were detected in an estrogen receptor-positive breast cancer cell line, MCF-7, and in an androgen-independent prostate cancer cell line, DU-145. Interestingly, the wild-type BRCA2 transcript was barely detectable in DU145, which could be used as a model system for future investigations on BRCA2 delta 12 function. Taken together, our data suggest disruption of BRCA1 and/or BRCA2 gene expression in certain epithelial cancer cell lines of the ovary, prostate, and breast. Because wild-type BRCA1 and BRCA2 gene products increase during cell-cycle progression and are believed to exert growth-inhibitory action, enhanced expression of these genes in cancer cells may represent a negative feedback mechanism for curbing proliferation in fast-growing cells. At present, the functionality of BRCA2 delta 12 remains elusive.
Mol Carcinog 2000 Aug
PMID:Altered expression of BRCA1, BRCA2, and a newly identified BRCA2 exon 12 deletion variant in malignant human ovarian, prostate, and breast cancer cell lines. 1097 93

The ADAMs are a multi-functional gene family, some of which have been shown to play a role in diverse biological processes such as fertilization, myogenesis, neurogenesis and the activation of growth factors/immune regulators such as TNF-alpha. So-named because they possess both A Disintegrin And Metalloprotease domain, the ADAMs have potential implications for the metastasis of human tumour cells via cell adhesion and protease activities. However, no studies have yet comprehensively examined the expression or regulation of ADAMs in solid tumours. Therefore, the aim of this study was to examine the expression of the ADAMs in human prostate cancer cell lines and to examine their possible regulation by androgen, a primary hormonal regulator of prostate cancer cell proliferation and metastasis. Applying RT-PCR, ADAM-9, -10, -11, -15 and -17 mRNA expression was found in the androgen-dependent prostate cancer cell lines, LNCaP and ALVA-41 and the androgen-independent cell lines, DU-145 and PC-3. Northern blotting of LNCaP cell total RNA revealed transcripts for ADAM-9 (3.8 kb), ADAM-10 (4.4, 3.2 and 0.54 kb), ADAM-15 (3 kb) and ADAM-17 (4 and 2.6 kb). ADAM-11 transcript was not detected by Northern blotting possibly due to low levels of ADAM-11 mRNA expression. This is the first report of ADAM expression in prostate cancer cell lines. Since androgens are implicated in prostate cancer cell growth and maintenance, the regulation of ADAMs by dihydrotestosterone (DHT) was investigated in the androgen-dependent cell line LNCaP. It was shown by quantitative RT-PCR using continuous fluorescence monitoring that ADAM-10 mRNA expression was regulated in a bell shaped, dose-dependent manner by DHT. Maximum stimulation was observed at 1.0 nM DHT (5-fold significant increase). For ADAM-9 mRNA, a significant upregulation was found at 1.0 and 10 nM (1.5-1.7-fold increase). In contrast, ADAM-17 mRNA, was significantly inhibited at 0.1 and 1.0 nM (1.7-fold decrease). This is the first report, to our knowledge, illustrating hormonal regulation of ADAM mRNA. The novel data described here also provide a strong stimulus to the development of specific quantitative and functional assays for particular ADAMs. These assays, which are not yet available, are required to enable subsequent investigation, both in vitro and in vivo, of the specific roles of each ADAM in prostate cancer cell proliferation, cell motility and invasion.
Mol Cell Endocrinol 2000 Sep 25
PMID:The expression of the ADAMs proteases in prostate cancer cell lines and their regulation by dihydrotestosterone. 1100 May 16

Several laboratories have attempted with little success to induce Fas-mediated apoptosis in prostate cancer (PCa) cells, using different external Fas agonists, i.e., anti-Fas antibodies and membrane-bound FasL. The present study confirms these earlier results using the anti-Fas antibody CH-11 in five human PCa cell lines (PPC-1, LNCaP, PC-3, TSU-Pr1, and DU145). However, intracellular murine FasL expression induced Fas-mediated apoptosis in all CH-11-resistant cell lines. Adenovirus (AdGFPFasL(TET)) was used to deliver a Murine FasL-GFP fusion gene into human PCa cells resulting in 70-98% apoptosis at 48 h as determined by the MTS assay. DU145 and PPC-1 cells treated with AdGFPFasL(TET) stained positive for the TUNEL assay, indicating that cell death was via apoptosis. Using immunofluorescent microscopy, Fas and GFPFasL colocalized to the same intracellular compartment. The anti-Fas neutralizing antibody ZB-4 was unable to block AdGFPFasL(TET)-mediated cell death, suggesting that intracellular FasL may ligate Fas within the Golgi and/or endoplasmic reticulum. This is the first evidence suggesting that these two molecules interact prior to cell surface presentation. Collectively, these findings indicate that intracellular GFPFasL expression is superior to CH-11 at inducing Fas-mediated apoptosis in human PCa cells and may allow use of AdGFPFasL(TET) for PCa gene therapy.
Mol Ther 2000 Oct
PMID:Intracellular Fas ligand expression causes Fas-mediated apoptosis in human prostate cancer cells resistant to monoclonal antibody-induced apoptosis. 1102 Mar 50

1,25-Dihydroxyvitamin-D3 [1,25(OH)2D3], the active hormonal metabolite of vitamin D, acts through a specific nuclear receptor to inhibit proliferation and promote differentiation of several tumor cell types including the LNCaP, DU145 and PC-3 prostate cancer cell lines as well as primary prostate tumor lines. 1,25(OH)2D3 can also decrease invasion of breast and prostate cancer cell lines in vitro. We confirm this latter finding in the DU145 and PC-3 prostate cancer cell lines, and further show that 1,25(OH)2D3 inhibits overall invasion, cell adhesion and migration to the basement membrane matrix protein laminin. These changes appear to be due in part to a 1,25(OH)2D3-induced decrease in expression of alpha6 and beta4 integrins, both of which are receptors for laminin and associated with increased migration and invasion of prostate cancer cells in vitro. Blocking function of these particular integrins with antibodies inhibits both adhesion and migration of the cells. Collectively, these data demonstrate that 1,25(OH)2D3, in addition to decreasing proliferation of tumor cells, can also inhibit prostate cancer cell invasion through modulation of select cell surface adhesion molecules.
Mol Cell Endocrinol 2000 Jun
PMID:1,25-Dihydroxyvitamin D3 decreases human prostate cancer cell adhesion and migration. 1102 65


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