Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferons (IFNs) are known to possess potent antitumor properties. Previous studies have indicated that IFNs are capable of modulating the expression of various tumor suppressor genes and oncogenes. In this study, we looked at the effect of IFN-gamma on the neu/HER-2 proto-oncogene in the DU145, LNCaP, and PC-3 prostate cancer cell lines. IFN-gamma inhibited cell proliferation in both DU145 and PC-3 cells in a dose-dependent manner, whereas no inhibition of proliferation was seen in LNCaP cells. Correspondingly, IFN-gamma treatment of DU145 and PC-3 cells resulted in an increased production of the cyclin-dependent kinase inhibitor p21(WAF1), whereas no increase in p21(WAF1) was seen in LNCaP cells. In addition, IFN-gamma induced phosphorylation of signal transducer and activator of transcription (STAT) 1 in DU145 and PC-3 cells, but not in LNCaP cells. Consistent with these findings, we found that IFN-gamma treatment of DU145 and PC-3 cells caused a reduction in neu/HER-2 expression, with no change seen in the LNCaP cell line. Transfection and overexpression of the transcriptional coactivator p300 in PC-3 cells suppressed the reduction in neu/HER-2 expression after IFN-gamma treatment, suggesting a role for p300 in neu/HER-2 expression. The antiproliferative activity and p21(WAF1) production of these cells after IFN-gamma treatment were found to be reduced as well. We propose that the down-regulation of neu/HER-2 by IFN-gamma occurs via the interaction of phosphorylated STAT1 with p300 because IFN-gamma activities requiring phosphorylated STAT1 are reduced in cells overexpressing p300. These findings suggest that neu/HER-2 may play a role in the growth of some prostate cancers and that IFN-gamma may suppress such cancers by down-regulation of neu/HER-2.
 ...
PMID:Down-regulation of neu/HER-2 by interferon-gamma in prostate cancer cells. 1091 67

We previously reported that expression of the breast cancer susceptibility gene BRCA1 strongly inhibits the transcriptional activity of the estrogen receptor (ER-alpha) in human breast and prostate cancer cell lines but only weakly inhibits ER-alpha activity in cervical cancer cells (S. Fan et al., Science (Wash. DC), 284: 1354-1356, 1999). We now report that the ability of BRCA1 to repress ER-alpha activity correlates with its ability to induce down-regulation of the cellular levels of the transcriptional coactivator p300 in breast and prostate, but not in cervical cancer cells. On the other hand, BRCA1 failed to alter the expression of the CREB binding protein (CBP), the structural and functional homologue of p300, in any of these cell types. Ectopic expression of either p300 or CBP "rescued" (i.e., reversed) the BRCA1 inhibition of ER-alpha activity, whereas two other nuclear receptor coactivators, the p300/CBP-associated factor (PCAF) and the glucocorticoid receptor-interacting protein-1 (GRIP1), failed to rescue the ER-alpha activity. The rescue function mapped to the cysteine-histidine rich domain CH3, a region of p300/CBP that we found to interact directly with the conserved COOH-terminal activation domain (AF-2) of ER-alpha. p300 and ER-alpha were also found to interact in vivo and to colocalize within the nucleus in breast cancer cells. These findings suggest that the cofactors p300 and CBP modulate the ability of the BRCA1 protein to inhibit ER-alpha signaling. They further suggest that the BRCA1 inhibition of ER-alpha activity may be attributable, at least in part, to the down-regulation of p300.
 ...
PMID:p300 Modulates the BRCA1 inhibition of estrogen receptor activity. 1178 71

NKX3.1, 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. A C-->T polymorphism at nucleotide 154 (NKX3.1 C154T) is present in approximately 11% of healthy men with equal distribution among whites and blacks. In a cohort of 1253 prostate cancer patients and age-matched controls, the presence of the polymorphism was associated with a 1.8-fold risk of having stage C or D prostate cancer or Gleason score > or =7 (confidence interval, 1.01-3.22). The NKX3.1 C154T polymorphism codes for a variant protein that contains an arginine-to-cysteine substitution at amino acid 52 (R52C) adjacent to a protein kinase C phosphorylation site at serine 48. Substitution of cysteine for arginine 52 or of alanine for serine 48 (S48A) reduced phosphorylation at serine 48 in vitro and in vivo. Phosphorylation of wild-type NKX3.1, but not of NKX3.1 R52C or NKX3.1 S48A, diminished binding in vitro to a high-affinity DNA binding sequence. NKX3.1 also serves as a transcriptional coactivator of serum response factor. Treatment of cells with 12-O-tetradecanoylphorbol-13-acetate to phosphorylate NKX3.1 had no effect on NKX3.1 coactivation of serum response factor. Neither the R52C nor the S48A substitution affected serum response factor coactivation by NKX3.1 We conclude that the polymorphic NKX3.1 allele codes for a variant protein with altered DNA binding activity that may affect prostate cancer risk.
 ...
PMID:Occurrence of NKX3.1 C154T polymorphism in men with and without prostate cancer and studies of its effect on protein function. 1198 Jun 64

Androgen receptor trapped clone-27 (ART-27) is a newly described transcriptional coactivator that binds to the N terminus of the androgen receptor (AR). Given the vital importance of AR signaling in prostate growth and differentiation, we investigated the role of ART-27 in these processes. Immunohistochemical studies indicate that ART-27 protein is expressed in differentiated epithelial cells of adult human prostate and breast tissue. In prostate, ART-27 is abundant in AR-positive prostate luminal epithelial cells, in contrast to the stroma, where cells express AR but not ART-27. The use of a rat model of androgen depletion/reconstitution indicates that ART-27 expression is associated with the elaboration of differentiated prostate epithelial cells. Interestingly, regulated expression of ART-27 in the androgen-sensitive LNCaP prostate cancer cell line inhibits androgen-mediated cellular proliferation and enhances androgen-mediated transcription of the prostate-specific antigen (PSA) gene. Consistent with a growth suppressive function, we show that ART-27 expression levels are negligible in human prostate cancer. Importantly, examination of ART-27 protein expression in early fetal prostate development demonstrates that ART-27 is detected only when the developing prostate gland has proceeded from a solid mass of undifferentiated cells to a stage in which differentiated luminal epithelial cells are evident. Thus, ART-27 is an AR cofactor shown to be subject to both cell type and developmental regulation in humans. Overall, the results suggest that decreased levels of ART-27 protein in prostate cancer tissue may occur as a result of de-differentiation, and indicate that ART-27 is likely to regulate a subset of AR-responsive genes important to prostate growth suppression and differentiation.
 ...
PMID:ART-27, an androgen receptor coactivator regulated in prostate development and cancer. 1471 28

The transcriptional activity of the androgen receptor (AR) is regulated by interaction with various coregulators, one of which is beta-catenin. Interest in the role of beta-catenin in prostate cancer has been stimulated by reports showing that it is aberrantly expressed in the cytoplasm and/or nucleus in up to 38% of hormone-refractory tumours and that overexpression of beta-catenin results in activation of AR transcriptional activity. We have examined the effect of depleting endogenous beta-catenin on AR activity using Axin and RNA interference. Axin, which promotes beta-catenin degradation, inhibited AR transcriptional activity. However, this did not require the beta-catenin-binding domain of Axin. Depletion of beta-catenin using RNA interference increased, rather than decreased, AR activity, suggesting that endogenous beta-catenin is not a transcriptional coactivator for the AR. The glycogen synthase kinase-3 (GSK-3)-binding domain of Axin prevented formation of a GSK-3-AR complex and was both necessary and sufficient for inhibition of AR-dependent transcription. A second GSK-3-binding protein, FRAT, also inhibited AR transcriptional activity, as did the GSK-3 inhibitors SB216763 and SB415286. Finally, inhibition of GSK-3 reduced the growth of AR-expressing prostate cancer cell lines. Our observations suggest a potential new therapeutic application for GSK-3 inhibitors in prostate cancer.
 ...
PMID:Inhibition of glycogen synthase kinase-3 represses androgen receptor activity and prostate cancer cell growth. 1536 37

Standard therapy for nonorgan confined prostate cancer aims to block the production or action of androgens. Although initially successful, antiandrogen therapy eventually fails and androgen depletion independent (ADI) disease emerges. Remarkably, ADI prostate cancers still rely on a functional androgen receptor (AR). Aberrant expression of coregulatory proteins required for the formation of productive AR transcriptional complexes is critical for ADI AR activation. Previously, we have shown that the transcriptional coactivator p300 is required for ADI activation of the AR and is up-regulated in prostate cancer, in which its expression is associated with cell proliferation and predicts aggressive tumor features. The mechanism responsible for the deregulated expression of p300, however, remains elusive. Here, we show that p300 expression in prostate cancer cells is subject to androgen regulation. In several prostate cancer model systems, addition of synthetic and natural androgens led to decreased expression of p300 in a time-dependent and dose-dependent manner. Experiments using AR antagonists or small interfering RNA targeting the AR revealed that down-regulation of p300 depends entirely on the presence of a functional AR. It is noteworthy that androgens down-regulated p300 protein expression while leaving messenger levels unaltered. Conversely, both short-term and long-term androgen deprivation resulted in marked up-regulation of p300 expression. The androgen deprivation-induced increase in p300 expression was not affected by the addition of cytokines or growth factors or by cotreatment with antiandrogens. Moreover, increased p300 expression upon androgen starvation is crucial for prostate cancer cell proliferation, as loss of p300 expression severely reduces expression of cyclins governing G(1)-S and G(2)-M cell cycle transition and decreases 5-bromo-2'-deoxyuridine incorporation.
 ...
PMID:Androgen deprivation increases p300 expression in prostate cancer cells. 1740 53

The androgen receptor (AR) is a member of the nuclear steroid hormone receptor family and is thought to play an important role in the development of both androgen-dependent and androgen-independent prostatic malignancy. Elucidating roles by which cofactors regulate AR transcriptional activity may provide therapeutic advancement for prostate cancer (PCa). The DEAD box RNA helicase p68 (Ddx5) was identified as a novel AR-interacting protein by yeast two-hybrid screening, and we sought to examine the involvement of p68 in AR signaling and PCa. The p68-AR interaction was verified by colocalization of overexpressed protein by immunofluorescence and confirmed in vivo by coimmunoprecipitation in the PCa LNCaP cell line. Chromatin immunoprecipitation in the same cell line showed AR and p68 recruitment to the promoter region of the androgen-responsive prostate-specific antigen (PSA) gene. Luciferase reporter, minigene splicing assays, and RNA interference (RNAi) were used to examine a functional role of p68 in AR-regulated gene expression, whereby p68 targeted RNAi reduced AR-regulated PSA expression, and p68 enhanced AR-regulated repression of CD44 splicing (P = 0.008). Tyrosine phosphorylation of p68 was found to enhance coactivation of ligand-dependent transcription of AR-regulated luciferase reporters independent of ATP-binding. Finally, we observe increased frequency and expression of p68 in PCa compared with benign tissue using a comprehensive prostate tissue microarray (P = 0.003; P = 0.008). These findings implicate p68 as a novel AR transcriptional coactivator that is significantly overexpressed in PCa with a possible role in progression to hormone-refractory disease.
 ...
PMID:The RNA helicase p68 is a novel androgen receptor coactivator involved in splicing and is overexpressed in prostate cancer. 1882 51

Androgen deprivation is still the standard systemic therapy for metastatic prostate cancer (PCa), but patients invariably relapse with a more aggressive form of PCa termed hormone refractory, androgen independent, or castration resistant PCa (CRPC). Significantly, the androgen receptor (AR) is expressed at high levels in most cases of CRPC, and these tumors resume their expression of multiple AR-regulated genes, indicating that AR transcriptional activity becomes reactivated at this stage of the disease. The molecular basis for this AR reactivation remains unclear, but possible mechanisms include increased AR expression, AR mutations that enhance activation by weak androgens and AR antagonists, increased expression of transcriptional coactivator proteins, and activation of signal transduction pathways that can enhance AR responses to low levels of androgens. Recent data indicate that CRPC cells may also carry out intracellular synthesis of testosterone and DHT from weak adrenal androgens and may be able to synthesize androgens from cholesterol. These mechanisms that appear to contribute to AR reactivation after castration are further outlined in this review.
 ...
PMID:Mechanisms mediating androgen receptor reactivation after castration. 1911 96

Chromosomal aberrations involving genes encoding members of the p160/SRC transcriptional coactivator family such as AIB1/ACTR and TIF2 implicated the coactivators in malignancy of human cells. Significant progress has been made in the last decade toward uncovering their roles in the development and progression of solid tissue tumors as well as leukemia and understanding of the underlying molecular mechanisms. Here, we review their genetic aberrations and dysregulation in expression in breast cancer, prostate cancer, and other nonhormone-responsive cancers. The experimental evidence gathered from studies using cell culture and animal models strongly supports a critical and, in some circumstances, their oncogenic function. We summarize results that the SRCs may contribute to tumorigenesis and disease progression through transcription factors such as E2F, PEA3, and AP-1 and through an intimate control of signaling pathways of growth factors-Akt and the receptor tyrosine kinases. The finding that a recently identified nuclear receptor coregulator ANCCA, like the SRCs, is frequently overexpressed in many types of cancers again underscores their broader roles in cancer.
 ...
PMID:The roles and action mechanisms of p160/SRC coactivators and the ANCCA coregulator in cancer. 2037 7

Patients with metastatic prostate cancer who undergo androgen-ablation therapy invariably relapse and develop incurable castration-resistant disease. Activation of the prosurvival Akt pathway accompanies androgen ablation. We discovered that the androgen receptor induces the expression of the tumor suppressor inositol polyphosphate 4-phosphatase type II (INPP4B) but not PTEN in prostate cancer cells. Optimal induction of INPP4B by an androgen receptor required the expression of the transcriptional coactivator NCoR. INPP4B dephosphorylates phosphatidylinositol-3, 4-bisphosphate, which leads to reduced phosphorylation and activity of Akt. In support of a key role for INPP4B in Akt control, INPP4B depletion activated Akt and increased cellular proliferation. The clinical significance of INPP4B in androgen-dependent prostate cancers was determined in normal or primary tumor prostate tissues derived from radical prostatectomy specimens. In primary tumors, the expression of both INPP4B and PTEN was substantially reduced compared with normal tissue. Further, the decreased expression of INPP4B reduced the time to biochemical recurrence. Thus, androgen ablation can activate the Akt pathway via INPP4B downregulation, thereby mitigating the antitumor effects of androgen ablation. Our findings reinforce the concept that patients undergoing androgen ablation may benefit from Akt-targeting therapies.
 ...
PMID:Decreased expression and androgen regulation of the tumor suppressor gene INPP4B in prostate cancer. 2122 58


1 2 3 Next >>