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)

Prostatic epithelial cells that are capable of surviving in the absence of androgenic steroids were found to express protein kinase Cepsilon (PKCepsilon), an oncogenic protein capable of promoting autocrine cell-signaling events. Gene transfer experiments demonstrated that PKCepsilon overexpression was sufficient to transform androgen-dependent LNCaP cells into an androgen-independent variant that rapidly initiated tumor growth in vivo in both intact and castrated male nude mice. This transformation was associated with an accelerated rate of androgen-independent LNCaP cell proliferation, resistance to apoptosis, hyperphosphorylation of the mitogen-activated protein kinase extracellular signal-regulated kinase and transcriptional repressor protein retinoblastoma, and increased expression of E2F-1 and other 5'-cap-dependent mRNAs, including the G(1) cyclins, c-myc, and caveolin-1. Coimmunoprecipitation experiments indicated that PKCepsilon was associated with members of the extracellular signal-regulated kinase signaling cascade and the scaffolding protein caveolin-1. Caveolin-1, produced by LNCaP cells overexpressing PKCepsilon, was released into the medium, possibly through a Golgi-independent route, and significant growth inhibition was observed when these cells were cultured in the presence of an anti-caveolin-1 antiserum. Finally, antisense experiments established that endogenous PKCepsilon plays an important role in regulating the growth and survival of androgen-independent prostate cancer cells. This study provides several independent lines of evidence supporting the hypothesis that PKCepsilon expression may be sufficient to maintain prostate cancer growth and survival after androgen ablation.
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PMID:Protein kinase cepsilon has the potential to advance the recurrence of human prostate cancer. 1195 6

The recent finding of overexpression of the polycomb group transcriptional repressor EZH2 in prostate cancer raises the possibility that transcriptional regulation at the chromatin level may play a role in the development of the metastatic phenotype and suggests new avenues of exploration with respect to patient stratification and therapeutics.
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PMID:The EZH2 polycomb transcriptional repressor--a marker or mover of metastatic prostate cancer? 1245 Jul 88

Prostate apoptosis response-4 (par-4) is a pro-apoptotic gene identified in prostate cancer cells undergoing apoptosis. Par-4 protein, which contains a leucine zipper domain at the carboxy-terminus, functions as a transcriptional repressor in the nucleus. Par-4 selectively induces apoptosis in androgen-independent prostate cancer cells and Ras-transformed cells but not in androgen-dependent prostate cancer cells or normal cells. Cells that are resistant to apoptosis by Par-4 alone, however, are greatly sensitized by Par-4 to the action of other pro-apoptotic insults such as growth factor withdrawal, tumor necrosis factor, ionizing radiation, intracellular calcium elevation, or those involved in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and stroke. Apoptosis induction by Par-4 involves a complex mechanism that requires activation of the Fas death receptor signaling pathway and coparallel inhibition of cell survival NF-kappaB transcription activity. The unique ability of Par-4 to induce apoptosis in cancer cells but not normal cells and the ability of Par-4 antisense or dominant-negative mutant to abrogate apoptosis in neurodegenerative disease paradigms makes it an appealing candidate for molecular therapy of cancer and neuronal diseases.
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PMID:Apoptosis by Par-4 in cancer and neurodegenerative diseases. 1256 19

The Polycomb Group Protein EZH2 is a transcriptional repressor involved in controlling cellular memory and has been linked to aggressive prostate cancer. Here we investigate the functional role of EZH2 in cancer cell invasion and breast cancer progression. EZH2 transcript and protein were consistently elevated in invasive breast carcinoma compared with normal breast epithelia. Tissue microarray analysis, which included 917 samples from 280 patients, demonstrated that EZH2 protein levels were strongly associated with breast cancer aggressiveness. Overexpression of EZH2 in immortalized human mammary epithelial cell lines promotes anchorage-independent growth and cell invasion. EZH2-mediated cell invasion required an intact SET domain and histone deacetylase activity. This study provides compelling evidence for a functional link between dysregulated cellular memory, transcriptional repression, and neoplastic transformation.
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PMID:EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. 1450 Sep 7

The androgen receptor (AR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and plays a key role in the development and progression of prostate cancer. Current therapies include the use of antiandrogens aimed at inhibiting the transcriptional activation of AR-regulated genes by AR. Here, we explore a strategy aimed at obtaining silencing of AR-regulated genes, based on the properties of the transcriptional repressor promyelocytic leukamia zinc-finger protein (PLZF). In order to do this, we have made a fusion protein between PLZF and AR, named PLZF-AR, and show that PLZF-AR is able to bring about silencing of genomically encoded AR-regulated genes and inhibit the androgen-regulated growth of LNCaP prostate cancer cells. Together, our results show that this strategy is able to bring about potent repression of AR-regulated responses and, therefore, could be of value in the development of new therapies for prostate cancer.
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PMID:Silencing of androgen-regulated genes using a fusion of AR with the PLZF transcriptional repressor. 1533 66

Prostate cancer is the most frequently diagnosed cancer in men and the second leading cause of male cancer death in the United States. Early detection and improved procedures for surgical intervention and radiation therapy have reduced the fatalities; however, there is no effective cure for men with advanced disease and additional therapy is urgently needed. We have previously shown that MBP-1 acts as a general transcriptional repressor and exerts an antiproliferative effect on several human cancer cells. MBP-1 possesses two repressor domains, located at the amino and carboxyl termini. In this study, we have examined the potential of the repressor domains of MBP-1 as a gene therapeutic candidate in regression of prostate tumor growth. Our results suggested that replication-deficient adenovirus-mediated delivery of amino-terminal (MBP-AR) or carboxyl-terminal (MBP-CR) repressor domain of MBP-1 exerted an antiproliferative effect, like the full-length MBP-1, and induced caspase-independent apoptosis in prostate cancer cells. Next, we investigated the therapeutic effectiveness of MBP-1 repressor domain on prostate tumors. When tested in human tumor xenografts in nude mice, MBP-CR suppressed prostate tumor growth more effectively than full-length MBP-1, whereas MBP-AR delayed prostate tumor growth. Together, these results suggested that MBP-CR expression has an antiproliferative effect in human prostate cancer cells, being more effective than the full-length MBP-1 in preventing tumor growth.
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PMID:Carboxyl-terminal repressor domain of MBP-1 is sufficient for regression of prostate tumor growth in nude mice. 1570 66

Prostate cancer is the most common and invasive type of cancer among American men, and the second leading cause of cancer-elated deaths in the United States. Unfortunately, an effective therapeutic regimen is still lacking for advance stages of the disease. Recently, MEK5 has been shown to overexpress in prostate cancer and is associated with poor survival outcome. MEK5 exists as alpha- and beta-isoforms. MEK5alpha induces cell proliferation by activating its downstream molecules, whereas MEK5beta expression is associated with inhibition of cell growth. We have recently shown that exogenous expression of c-myc promoter-binding protein 1 (MBP-1) induces prostate cancer cell death (Ghosh, A. K., Steele, R., and Ray, R. B. (2005) Cancer Res. 65, 718-721). In this study, we have investigated whether inhibition of MEK5 signaling pathway can modulate prostate cancer cell growth. MBP-1 is a general transcriptional repressor and modulates a number of cellular genes. Therefore, we examined the endogenous expression status of MEK5 in androgen-independent prostate cancer cells upon recombinant adenovirus-mediated introduction of MBP-1. Our results demonstrated that MBP-1 expression reduced the endogenous MEK5alpha protein level; on the other hand, MEK5beta expression was enhanced significantly. Transduction of MBP-1 modulates the downstream signaling molecules of MEK5, such as activation of the cyclin D1 promoter and MEF2C transcriptional activities in androgen-independent prostate cancer cells. MBP-1 expression also modulates MEK5-mediated activation of NF-kappaB. Further analysis suggested that MBP-1 physically associates with MEK5 and induces proteasome-mediated degradation of the MEK5 protein, which appears to occur independently of ubiquitination. Together, our results suggested a novel role of MBP-1 for suppression of prostate cancer cell growth by regulating the MEK5-mediated signaling pathway.
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PMID:c-myc Promoter-binding protein 1 (MBP-1) regulates prostate cancer cell growth by inhibiting MAPK pathway. 1580 19

We have previously shown that MBP-1 acts as a general transcriptional repressor, and forced expression of MBP-1 exerts an anti-proliferative effect on a number of human cancer cells. In this report, we have investigated the role of endogenous MBP-1 in cell growth regulation. For this, we generated human prostate cancer cells (PC3) stably transfected with short hairpin RNA targeting MBP-1. We have observed retarded growth and longer doubling time of MBP-1 knockdown PC3 cells as compared with control mock-transfected PC3 cells. Fluorescence-activated cell sorter analysis suggested that PC3 cells expressing MBP-1-specific small interfering RNA accumulated during G2/M phase of the cell cycle. Further analysis suggested that depletion of MBP-1 was associated with reduction of cyclin A and cyclin B1 expression when compared with that of the control cells. A delayed induction of cyclin A and B1 expression was observed in MBP-1-depleted PC3 cells (PC3-4.2) upon serum stimulation, although the level of expression was much lower than that of control PC3 cells. Supplementation of MBP-1 in PC3-4.2 cells restored cyclin A and cyclin B1 expression. Together, these results suggest that knockdown of MBP-1 in prostate cancer cells perturbs cell proliferation by inhibiting cyclin A and cyclin B1 expression.
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PMID:Knockdown of MBP-1 in human prostate cancer cells delays cell cycle progression. 1676 17

The EVI1 transcriptional repressor is critical to the normal development of a variety of tissues and participates in the progression of acute myeloid leukaemias. The repressor domain (Rp) was used to screen an adult human kidney yeast two-hybrid library and a novel binding partner designated ubiquitously expressed transcript (UXT) was isolated. Enforced expression of UXT in Evi1-expressing Rat1 fibroblasts suppresses cell transformation and UXT may therefore be a negative regulator of Evi1 biological activity. The Rp-binding site for UXT was determined and non-UXT-binding Evi1 mutants (Evi1Delta706-707) were developed which retain the ability to bind the corepressor mCtBP2. Evi1Delta706-707 transforms Rat1 fibroblasts, showing that the interaction is not essential for Evi1-mediated cell transformation. However, Evi1Delta706-707 produces an increased proportion of large colonies relative to wild-type, showing that endogenous UXT has an inhibitory effect on Evi1 biological activity. Exogenous UXT still suppresses Evi1Delta706-707-mediated cell transformation, indicating that it inhibits cell proliferation and/or survival by both Evi1-dependent and Evi1-independent mechanisms. These observations are consistent with the growth-suppressive function attributed to UXT in human prostate cancer. Our results show that UXT suppresses cell transformation and might mediate this function by interaction and inhibition of the biological activity of cell proliferation and survival stimulatory factors like Evi1.
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PMID:UXT interacts with the transcriptional repressor protein EVI1 and suppresses cell transformation. 1763 84

Diminished expression of the metastasis suppressor protein RKIP was previously reported in a number of cancers. The underlying mechanism remains unknown. Here, we show that the expression of RKIP negatively correlates with that of Snail zinc-transcriptional repressor, a key modulator of normal and neoplastic epithelial-mesenchymal transition (EMT) program. With a combination of loss-of-function and gain-of-function approaches, we showed that Snail repressed the expression of RKIP in metastatic prostate cancer cell lines. The effect of Snail on RKIP was on the level of transcriptional initiation and mediated by a proximal E-box on the RKIP promoter. Our results therefore suggest that RKIP is a novel component of the Snail transcriptional regulatory network important for the progression and metastasis of cancer.
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PMID:Snail is a repressor of RKIP transcription in metastatic prostate cancer cells. 1795 20


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