Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The polypeptide growth factors insulin-like growth factor I (IGF-I), epidermal growth factor (EGF), and transforming growth factor-alpha (TGF-alpha); second-messenger cyclic adenosine monophosphate (cAMP): protein kinase activators; and neurotransmitters were found to activate the estrogen (ER), progesterone (PR), and glucocorticoid receptor (GR) either in the absence of their natural ligands or synergistically with the respective hormone. There is now evidence of coupling of signaling pathways involving the androgen receptor (AR). Three polypeptide growth factor, IGF-I, keratinocyte growth factor (KGF), and EGF, stimulated AR-mediated reporter-gene transcription in the absence of androgen in DU-145 cells, which were cotransfected with the reporter gene and an AR expression vector. IGF-I effects were observed irrespective of the promoter driving the reporter gene. This growth factor increased the prostate-specific antigen (PSA) level in LNCaP cells, which contain endogenous AR. In CV-1 cells, which transiently express the AR, second-messenger cAMP potentiated effects of testosterone in stimulation of AR-mediated reporter-gene activity. Inhibition of androgen-stimulated chloramphenicol acetyltransferase (CAT) activity in the LNCaP cell line was achieved with retinoic acid. Stimulation and inhibition of prostatic carcinoma cell growth by polypeptide growth factors and cellular regulators may depend on the presence of the AR in an androgen-depleted environment.
 ...
PMID:Activation of the androgen receptor by polypeptide growth factors and cellular regulators. 858 Sep 99

These experiments were designed to examine the relationship between the effects of steroid hormones mediated by classic intracellular steroid hormone receptors and those mediated by a signaling system subserved at the plasma membrane by a receptor for sex hormone-binding globulin. It is known that unliganded sex hormone-binding globulin (SHBG) binds to a receptor (RSHBG) on prostate membranes. The RSHBG.SHBG complex is rapidly activated by estradiol to stimulate adenylate cyclase, with a resultant increase in intracellular cAMP. In this paper we examine the effect of this system on a prostate gene product known to be activated by androgens, prostate-specific antigen. In serum-free organ culture of human prostates, dihydrotestosterone caused an increase in prostate specific antigen secretion. This event was blocked by the anti-androgens cyproterone acetate and hydroxyflutamide. In the absence of androgens, estradiol added to prostate tissue, whose RSHBG was occupied by SHBG, reproduced the results seen with dihydrotestosterone. Neither estradiol alone nor SHBG alone duplicated these effects. The estradiol.SHBG-induced increase in prostate-specific antigen was not blocked by anti-estrogens, but was blocked both by anti-androgens and a steroid (2-methoxyestradiol) that prevents the binding of estradiol to SHBG. Furthermore, an inhibitor of protein kinase A prevented the estradiol.SHBG-induced increase in prostate-specific antigen but not that which followed dihydrotestosterone. These data indicate that there is a signaling system that amalgamates steroid-initiated intracellular events with steroid-dependent occurrences generated at the cell membrane and that the latter signaling system proceeds by a pathway that involves protein kinase A.
 ...
PMID:Estradiol activates the prostate androgen receptor and prostate-specific antigen secretion through the intermediacy of sex hormone-binding globulin. 905 66

p27kip1 (p27) protein is an inhibitor of cyclin and cyclin-dependent kinase complexes and prevents progression of cells from G1 to the S phase of the cell cycle. p27 might have tumor suppressor activity, and decreased p27 expression is associated with aggressive tumor behavior in several human malignancies. The object of this study was to evaluate p27 expression in prostatic adenocarcinoma treated by radical prostatectomy and to assess its association with numerous morphologic and clinical features. One hundred thirty-eight prostatic adenocarcinomas were evaluated for p27 expression by quantifying nuclear immunohistochemical staining. p27 expression was tested for association with patient age, family history of prostate cancer, preoperative serum prostate-specific antigen level, Gleason score, extraprostatic extension, seminal vesicle involvement, lymph node metastases, tumor-node-metastasis stage, DNA ploidy by flow cytometric analysis, and subclinical biochemical failure. p27 expression was analyzed as a continuous variable, and we also classified the tumors as low expressors (< 50% of cells p27 positive) or high expressors (> 50% of cells p27 positive) for comparison. Patients with adenocarcinomas that exhibited low p27 expression had higher mean Gleason scores than did high expressors (7 vs. 6.2, respectively; P = .002). Low p27 expression correlated with positive surgical margins (P = .05), seminal vesicle involvement (P = .007), lymph node metastasis (P = .03), and aneuploid cancers (P = .003), but it did not correlate with subclinical biochemical failure. p27 expression correlated with a number of prognostic morphologic features in prostatic adenocarcinoma, and the evaluation of p27 expression might provide additional prognostic information.
 ...
PMID:Expression of p27kip1 in prostatic adenocarcinoma. 957 81

Interleukin-6 (IL-6) levels are frequently elevated in sera of patients with metastatic prostate cancer. IL-6 receptors are expressed in prostate cancer cell lines, as well as in benign prostate hyperplasia and prostate cancer tissue specimens. The androgen receptor (AR) is a key transcription factor that is present in all stages of prostate carcinoma, even in therapy-refractory tumors. In an attempt to investigate possible cross-talk between IL-6 and androgen signal transduction cascades, we tested the effects of this cytokine on AR transcriptional activity. The regulation of AR activity by IL-6 was studied in DU-145 cells, which were cotransfected with the androgen-responsive reporter plasmid ARE2TATACAT and the AR expression vector pSG5AR. We show that IL-6 up-regulates AR activity in a ligand-independent manner, as well as synergistically, with very low doses of the synthetic androgen methyltrienolone (5-10 pM). Therefore, AR activation by IL-6 may be operative in prostate cancer patients who have decreased androgen levels because of androgen ablation therapy. The maximal induction of reporter gene activity by IL-6 alone (50 ng/ml) was 67% of that stimulated by 1 nM of methyltrienolone. The nonsteroidal antiandrogen bicalutamide (Casodex) nearly completely inhibited AR activation by IL-6. IL-6 effects on AR activity were also abolished or greatly reduced by inhibitors of protein kinase A and C and mitogen-activated protein kinase pathways. In concordance with the results obtained in DU-145 cells, IL-6 induced AR-regulated prostate-specific antigen mRNA and protein in LNCaP cells. Stimulation of prostate-specific antigen protein secretion by IL-6 was antagonized by bicalutamide and inhibitors of protein kinase A and mitogen-activated protein kinase signaling pathways. Taken together, our data show for the first time that IL-6 is a nonsteroidal activator of the AR and that this activation is implicated in the regulation of prostate-specific proteins. Keeping in mind that IL-6, its receptor, and the AR are expressed in prostate cancers, cross-talk between IL-6 and AR signaling pathways may have clinical significance.
 ...
PMID:Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor. 978 16

Transcription of the prostate-specific antigen (PSA) gene escapes regulation by androgens in advanced prostate cancer. To determine the molecular mechanism(s) of androgen-independent regulation of the PSA gene, the possibility that the androgen receptor (AR) is activated in the absence of androgen by stimulation of protein kinase A (PKA) was investigated. Activation of PKA by forskolin resulted in elevated expression of the PSA gene in androgen-depleted LNCaP cells, an effect that was blocked by the antiandrogen, bicalutamide. Further evidence that induction of PSA gene expression was dependent on AR was obtained from experiments using PC3 cells devoid of AR. Neither PSA, PB, nor ARR3 androgen-responsive reporters could be induced by activation of PKA in the absence of transfected AR. In addition, when nuclear AR from forskolin-treated LNCaP cells was incubated with oligonucleotides encoding an androgen response element of the PSA promoter and examined by electromobility shift assay, an increase in AR-androgen response element complex formation was observed. Lastly, cotransfection of an expression vector for a chimeric protein encoding the amino-terminal domain of the human AR linked to Gal4 and a 5xGal4UAS reporter gene construct resulted in activation of the amino-terminal domain of the AR by stimulation of PKA activity. These results demonstrate androgen-independent induction of PSA gene expression in prostate cancer cells by an AR-dependent pathway.
 ...
PMID:Androgen-independent induction of prostate-specific antigen gene expression via cross-talk between the androgen receptor and protein kinase A signal transduction pathways. 1007 69

To improve the therapy for prostate cancer, it will be necessary to address the problems of progression to androgen independence and the process of metastatic spread of tumour. The complexity of the latter condition is likely to mitigate against the immediate development of relevant therapeutic approaches. However, the basis of androgen independence appears to be a problem of simpler dimensions and more amenable to treatment with current therapeutic technology. Since early tumour progression can be detected by an incomplete prostate-specific antigen (PSA) response to androgen withdrawal therapy, a study of the molecular biology of PSA gene regulation may well provide insight into new methods for preventing or delaying this problem. Mounting evidence suggests that ligand-independent activation of the androgen receptor may be one underlying mechanism of androgen independence. In the absence of androgen, a compensatory increase in the activity of cAMP-dependent protein kinase (PKA) enhances the ability of the androgen receptor to bind to the response elements regulating PSA gene expression. The activation of the androgen receptor through up-regulation of the PKA signal transduction pathway involves the amino-terminus of the androgen receptor, the function of which may be altered either by modifications such as phosphorylation, or through interactions with co-regulators or other proteins. Of therapeutic interest is the fact that this effect can be counteracted experimentally by the anti-androgen, bicalutamide, and clinically by several other similar agents. We speculate that the inhibition of PKA-activated androgen receptor might also be accomplished by decoy molecules that can bind to the relevant activated site on the amino-terminus or competitively interact with proteins recruited by the PKA pathway that are responsible for activating the receptor in the absence of androgen. Such molecules might include small mimetic substances or agents that can gain access to the nucleus of the cell.
 ...
PMID:Prostate cancer: molecular biology of early progression to androgen independence. 1073 Sep 3

Genistein, a naturally occurring isoflavone found chiefly in soy products, reportedly has antiprostate cancer effects, but the mechanisms underlying these effects are unknown. We studied the antiproliferative and apoptosis-inducing effects of genistein in the androgen-sensitive human prostate cancer cell line LNCaP. Viable cell number was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay; cell-cycle progression and apoptosis were evaluated by flow cytometry; apoptosis was also assessed by a histone enzyme-linked immunosorbent assay; and the expression of several cell-cycle- and apoptosis-related genes and their gene products was determined by northern blot analysis, western blot analysis, and/or assays based on polymerase chain reaction. Physiologic concentrations of genistein (< or = 20 microM) decreased LNCaP viable cell number in a dose-dependent manner, induced a G(1) cell-cycle block, decreased prostate-specific antigen mRNA expression, and increased p27(KIP1) and p21(WAF1) (mRNA and protein) but had no effect on apoptosis or the mRNA expression of the apoptosis- and cell-cycle-related markers bcl-2, bax, Rb, and proliferating cell nuclear antigen. Higher concentrations of genistein (> 20 microM) did induce apoptosis. We conclude that genistein (at physiologic concentrations) exerts potent antiproliferative effects on LNCaP cells by inducing a G(1) cell-cycle block. The antiproliferative effects of genistein may be mediated by increased levels of p27(KIP1) and p21(WAF1), which are negative cell-cycle regulators that act as cyclin-dependent kinase inhibitors and that have been recently linked with prostate carcinogenesis. These findings may provide insights into the mechanisms underlying the apparent antiprostate cancer effects of soy consumption observed in epidemiologic studies.
 ...
PMID:Low-dose genistein induces cyclin-dependent kinase inhibitors and G(1) cell-cycle arrest in human prostate cancer cells. 1107 6

Interleukin-6 (IL-6) induces prostate cancer (CaP) cell proliferation in vitro. Several lines of evidence suggest that IL-6 may promote CaP progression through induction of an androgen response. In this work, we explored whether IL-6 induces androgen responsiveness through modulation of androgen receptor (AR) expression. We found that in the absence of androgen, IL-6 increased prostate-specific antigen (PSA) mRNA levels and activated several androgen-responsive promoters, but not the non-androgen responsive promoters in LNCaP cells. Bicalutamide, an antiandrogen, abolished the IL-6 effect and IL-6 could not activate the PSA and murine mammary tumor virus reporters in AR-negative DU-145 and PC3 cells. These data indicate the IL-6 induces an androgen response in CaP cells through the AR. Pretreatment of LNCaP cells with SB202190, PD98059, or tyrphostin AG879 [p38 mitogen-activated protein kinase (MAPK), MAP/extracellular signal-regulated protein kinase kinase 1/2, and ErbB2 MAPK inhibitors, respectively) but not wortmannin (PI3-kinase inhibitor) blocked IL-6-mediated induction of the PSA promoter, which demonstrates that IL-6 activity is dependent on a MAPK pathway. Finally, IL-6 activated the AR gene promoter, resulting in increased AR mRNA and protein levels in LNCaP cells. These results demonstrate that IL-6 induces AR expression and are the first report of cytokine-mediated induction of the AR promoter. Taken together, our results suggest that IL-6 induces AR activity through both increasing AR gene expression and activating the AR in the absence of androgen in CaP cells. These results provide a mechanism through which IL-6 may contribute to the development of androgen-independent CaP.
 ...
PMID:Interleukin-6 induces androgen responsiveness in prostate cancer cells through up-regulation of androgen receptor expression. 1141 May 19

Exisulind (Aptosyn, Cell Pathways, Inc.) is the first of a new class of targeted, pro-apoptotic drugs that show promise in the treatment of cancer. These agents induce apoptosis (i.e., programmed cell death) in a broad range of pre-cancerous and cancerous tissues without affecting normal cells. The antineoplastic effect of exisulind appears to be the result of activation of protein kinase G (PKG) which leads to multiple downstream effects culminating in apoptosis. Exisulind has demonstrated antineoplastic activity in solid tumour and haematological cancer cell lines and is an inhibitor of tumour growth in rodent models of colon, prostate, bladder, mammary and lung cancer. Preclinical data evaluating selective apoptotic antineoplastic drugs (SAANDs) in combination with various chemotherapy drugs indicates additive or synergistic antineoplastic effects. In clinical studies, exisulind prevented colorectal polyp formation in patients with familial adenomatous polyposis (FAP) over 24 months. In a randomised, placebo-controlled study of prostate cancer patients, exisulind inhibited the rise of prostate-specific antigen (PSA) in men with PSA progression after radical prostatectomy. Exisulind has been well-tolerated by most patients in clinical trials. In conclusion, preclinical evidence and early clinical results suggest that exisulind and other drugs in this class may have wide applications in treating cancer both as monotherapy and in combination with chemotherapy and other targeted agents.
 ...
PMID:Exisulind, a selective apoptotic antineoplastic drug. 1177 93

Semenogelins I and II are the quantitatively dominating proteins in human semen. They comprise the major part of the sperm-entrapping gel formed at ejaculation, which subsequently liquefies due to proteolysis of the gel-forming proteins by prostate-specific antigen (PSA). The mechanism behind gel formation and its physiological significance is not known. We have studied phosphorylation and dephosphorylation of human semenogelins. Both were phosphorylated by protein kinases A and C (PKA and PKC, respectively) at a rate about 5 times less than that of histone. For PKA, incorporated ((32)P)phosphate into semenogelin approached a maximum above 1 mol/mol. Corresponding values for phosphorylation of the semenogelins with PKC were greater than 10. There was no change in the sensitivity of phosphosemenogelins to proteolysis by PSA. Serine (PKA) and serine and threonine (PKC) were the phosphate-accepting amino acid residues, and all incorporated ((32)P)phosphate could be removed from the semenogelins with human acid phosphatase. Nil or very little phosphate could be detected in purified semenogelins isolated from seminal plasma. In vivo, about half the protein kinase activity in seminal plasma was bound to prostasomes. PKA but not PKC purified from prostasomes could phosphorylate specific substrates, but they could phosphorylate either of the semenogelins.
 ...
PMID:Exogenous protein kinases A and C, but not endogenous prostasome-associated protein kinase, phosphorylate semenogelins I and II from human semen. 1239 26


1 2 3 4 Next >>