Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate-specific antigen (PSA) is the most sensitive marker available for monitoring the progression of prostate cancer and response to therapy. In a previous study, we demonstrated tissue-specific expression of PSA glycoprotein and mRNA and its regulation through the androgen receptor. In this study, we examine the effects of protein kinase A (PKA) and protein kinase C (PKC) on the androgen regulation of PSA in a human adenocarcinoma cell line, LNCaP. Northern blot analysis demonstrated that forskolin, an activator of PKA, had no effect on the androgen regulation of PSA. However, the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA), a direct activator of PKC, showed a time- and dose-dependent repression of the androgen regulation of PSA glycoprotein and mRNA. The biologically inactive phorbol ester, 4 alpha-phorbol-12,13-didecanoate, had no effect. Staurosporine, a PKC inhibitor, blocked the TPA-mediated repression of the androgenic stimulation of PSA glycoprotein. In addition, the calcium ionophore, A23187, was able to simulate the actions of TPA, presumably through activation of PKC via calcium mobilization. In summary, the androgenic regulation of PSA protein and mRNA is repressed by tumor-promoting phorbol esters through the PKC pathway. This indicates that the effects of TPA may be secondary to repressed gene transcription or altered mRNA stability. In addition, this study emphasizes that the androgenic regulation of PSA is complex and may involve other extracellular transduction signals.
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PMID:Tumor-promoting phorbol ester down-regulates the androgen induction of prostate-specific antigen in a human prostatic adenocarcinoma cell line. 137 17

Androgen (R1881) induced transcriptional activity of the human androgen receptor, stably expressed in CHO cells, can be stimulated an extra 2-fold by the addition of the protein kinase C activator, 4 beta-phorbol 12-myristate 13-acetate (PMA). This extra stimulation is not observed when the protein kinase A activator bromoadenosine 3':5'-cyclic monophosphate (8-BrcAMP) is used. The transcriptional activity was measured using a reporter plasmid containing the MMTV-promoter, coupled to the luciferase gene. The effect of PMA on R1881-induced transcription was not due to a higher expression level of the androgen receptor. Also, no extra phosphorylation of the androgen receptor could be measured after incubation with PMA. When GRE-tk-LUC and PSA-LUC reporters were used, the synergistic effect of PMA could not be observed. The findings on the composite MMTV-LTR promoter can be explained by either a direct synergistic interaction between occupied AP-1 like responsive elements and the androgen receptor or via an unknown transcription factor activated by the PKC pathway and interacting with the androgen receptor.
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PMID:Synergism between androgens and protein kinase-C on androgen-regulated gene expression. 767 38

Elevation of intracellular calcium levels in the presence of normal androgen levels has been implicated in apoptotic prostate cell death. Since the androgen receptor (AR) plays a critical role in the regulation of growth and differentiation of the prostate, it was of interest to determine whether Ca2+ would affect the expression of androgen receptor messenger RNA (mRNA) and protein, thus affecting the ability of androgens to control prostate function. AR-positive human prostate cancer cells, LNCaP, were incubated with either the calcium ionophore A23187 or the intracellular endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin. Subsequently, AR mRNA and protein levels were assessed by Northern and Western blot analysis. Both A23187 and thapsigargin were found to down-regulate steady state AR mRNA levels in a time- and dose-dependent manner. AR mRNA began to decrease after 6-8 h of incubation with 10(-6) M A23187 or 10(-7) M thapsigargin, reaching a nadir at 16 and 10 h of incubation, respectively. In contrast, control mRNA (glyceraldehyde 3-phosphate dehydrogenase) did not change significantly during the treatments with either A23187 or thapsigargin. AR protein levels were found to be decreased after 12 h of incubation with either 10(-6) M A23187 or 10(-7) M thapsigargin. The decrease in AR mRNA and protein seemed to precede apoptosis, since neither A23187 (24 h) nor thapsigargin (30 h) was found to alter cell morphology within the treatment time. Cycloheximide and actinomycin D were unable to change the calcium-mediated decrease in AR mRNA, ruling out the necessity for de novo protein synthesis or a change in mRNA stability. Moreover, the decrease in AR mRNA induced by calcium does not seem to involve protein kinase C- or calmodulin-dependent pathways, since inhibitors of these cellular components had no effect. Nuclear run-on assays demonstrated little or no effects of either A23187 or thapsigargin treatment on AR gene transcription (8 h and 10 h). In conclusion, these studies show that intracellular calcium seems to be a potent regulator of AR gene expression in LNCaP cells.
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PMID:Calcium regulation of androgen receptor expression in the human prostate cancer cell line LNCaP. 772 Jun 67

12-O-tetradecanoyl phorbol ester (TPA) has profound cytotoxic effects on a human prostate cancer cell line, LNCaP. The TPA effect may be mediated via a protein kinase C (PKC) pathway, since staurosporine, a potent PKC inhibitor, could reverse the cell-killing effect. Our studies, based on cellular fragmentation, chromatin condensation, and nuclear fragmentation, suggest that the cell-killing effect is due to apoptosis. Moreover, we also examined expression of early growth response genes and androgen-induced genes in association with TPA-induced apoptosis. Northern blot analysis demonstrated that androgen induction of human glandular kallikrein-1 (hKLK2) mRNA was repressed by TPA in a concentration-dependent manner. A time course study showed that both hKLK2 and c-myc mRNAs were repressed by TPA as early as four hours. In contrast, the steady state mRNA levels for c-fos, c-jun, nerve growth factor induced gene A, and the orphan steroid receptor nur77 were rapidly induced within the first two hours of the treatment. Furthermore, transient co-transfection experiments demonstrated that c-fos and c-jun could repress androgen receptor-mediated gene induction. The above studies suggest that (1) the repression of androgen induction of gene expression by TPA-activated PKC is at least in part due to overexpression of c-jun and c-fos and (2) PKC may be a negative growth regulator in prostate cells.
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PMID:Tumor-promoting phorbol ester-induced cell death and gene expression in a human prostate adenocarcinoma cell line. 784 43

In rat thecal-interstitial cells (TIC), treatment with the synthetic androgen mibolerone has led to the documentation of an autoregulatory process for androgen production. In the present study, accumulated evidence has provided insight into the mechanisms of mibolerone action that control this process. Investigations using the nonsteroidal antiandrogen hydroxyflutamide were conducted to characterize mibolerone's mode of action. Hydroxyflutamide had differential effects on hCG action, the 1-microM dose stimulating hCG-induced androsterone synthesis by 27% and the 10-microM concentration decreasing the androgen levels by 84%. In addition, treatment with 1 microM hydroxyflutamide was effective in partially reversing the inhibitory action of mibolerone on hCG-stimulated androsterone production. Thus, the data indicated that mibolerone's mode of action may be mediated, at least in part, via the androgen receptor. The possibility that mibolerone had multiple sites of action prompted studies on the effectiveness of this androgen to alter various signaling pathways. Treatment with increasing concentrations (0.01-100 nM) of the phorbol ester 12-0-tetradecanoylphorbol 13-acetate (TPA), which activates protein kinase C, resulted in a 75% decrease in hCG-stimulated androgen production at a dose of 100 nM TPA. Treatment with mibolerone (100 nM) was unable to alter the action of TPA on androgen synthesis when doses of 1 and 10 nM TPA were employed. It was also found that Ca2+ can serve as a mediator of mibolerone action. Treatment with a 0.01-microM dose of A23187, a Ca2+ ionophore known to increase intracellular Ca2+, was ineffective in altering hCG-stimulated androsterone synthesis. The concurrent treatment of mibolerone (100 nM) and A23187 (0.01 microM) resulted in the potentiation of mibolerone's inhibitory effects on hCG-stimulated androgen production, thereby suggesting that mibolerone can stimulate Ca2+ influx. Additional studies revealed that the administration of a 1-microM dose of the L-type Ca2+ channel blocker verapamil to TIC cultures was able to partially block the inhibitory effect of mibolerone on androgen synthesis. Evidence for an additional site of mibolerone action was revealed through an analysis of the mRNA levels of P450scc and P450(17) alpha enzymes. Although hCG and insulin-like growth factor I treatment resulted in 20- and 32-fold increases in the amount of P450scc and P450(17) alpha mRNA, respectively, the addition of mibolerone (100 nM) reduced only P450(17) alpha mRNA levels by 91%. Overall, the evidence indicates that mibolerone has multiple sites of action in exerting its regulatory effect on androgen synthesis.
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PMID:Mechanisms of action for an androgen-mediated autoregulatory process in rat thecal-interstitial cells. 828 1

Citrate production is a major physiological function of the prostate that is regulated by testosterone and prolactin. Mitochondrial aspartate aminotransferase (mAAT) is a key enzyme in the metabolic pathway of prostate citrate production. In addition, prolactin stimulates expression of mAAT in the rat lateral prostate. In this report we establish the role of prolactin in the regulation of mAAT in two prostate cancer cell lines, LNCaP and PC-3. LNCaP cells respond to hormonal stimulation with increased secretion of prostate specific products. PC-3 cells, on the other hand, are testosterone independent and apparently do not respond to other growth factors either. Results showed that both LNCaP and PC-3 cells responded to prolactin with increased mAAT activity and an increased steady state level of mAAT mRNA. Prolactin also increased protein kinase C (PKC) activity in both these cell lines. Treatment of LNCaP and PC-3 cells with the phorbol ester 12-O-tetradecanoylphorbol (TPA) caused the same effect on mAAT activity and mRNA level as prolactin. The results suggest that the diacylglycerol-PKC signal transduction system mediates the prolactin effect on mAAT. In addition, these results also show that the prolactin effect on mAAT is independent of androgens since PC-3 cells reportedly lack androgen receptor expression. Thus, these results provide evidence that prolactin is a physiological regulator of prostate function in human as well as rat prostate. In addition, the results also show that though prostate cancer cells are androgen independent, they remain responsive to prolactin. This could have important implications for the treatment and management of prostate cancer.
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PMID:Prolactin regulation of mitochondrial aspartate aminotransferase and protein kinase C in human prostate cancer cells. 909 97

We have examined the human androgen receptor (hAR) for its ability to activate AR-dependent transcription of a transgene in a ligand-independent manner. The transcriptional activity was determined by analysis of chloramphenicol acetyltransferase (CAT) activity in T47D cells cotransfected with a plasmid expressing the hAR and a natural AR-regulated promoter (the MVDP androgen-dependent enhancer) ligated to the reporter CAT gene. In this study, the effects of the protein kinase C (PKC) activator 12-O-tetradecanoyphorbol-13 acetate (TPA) on AR activity were tested. We demonstrated that in the absence of androgen, TPA enhanced AR-mediated transactivation by 10-12-fold. This effect was specific of the PKC pathway since stimulation to the PKA pathway did not activate the unliganded AR. This ligand-independent pathway can function through another androgen-regulated promoter as shown by the use of the mouse mammary tumor virus MMTV-CAT reporter. The human glucocorticoid receptor (hGR) and the rabbit progesterone receptor (rPR) could not be activated by TPA, indicating that the effects are not universal for steroid receptors. A reporter plasmid containing the MVDP androgen response element (ARE) in front of the thymidine kinase promoter ligated to the CAT gene was activated by DHT but not by TPA, indicating that the context of the natural promoter is critical for ligand-independent activation of the AR. Exogenous c-jun enhanced transcriptional activation by the AR in a ligand-dependent manner, but had no effect in the absence of DHT. Base pair substitutions in both AR-binding (5'-TGTTCT-3' to 5'-TTTTTT-3') and NF1-binding (5'-GTGGCTG-3' to 5'-GTTTTTG-3') sites resulted in a loss of TPA responsiveness. Our results suggest that ligand-independent activation of the AR by TPA results from interaction of unliganded AR with other proteins in the transcription machinery.
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PMID:Phorbol ester causes ligand-independent activation of the androgen receptor. 978 Feb 30

The androgen receptor (AR) protein is an important transacting factor that is necessary for mediating gene expression of androgen-responsive genes. The expression of the AR gene is regulated by androgens and agents that utilize the calcium, protein kinase A, and protein kinase C pathways. Although the role of the calcium and protein kinase A pathways in the regulation of the AR gene has been investigated, the mechanism of regulation of AR through the protein kinase C pathway is not known. We have isolated the 5'-flanking region of the mouse AR gene and identified a consensus TPA (12-O-tetradecanoylphorbol 13-acetate)-response element (TRE). Transient transfection assays indicate that the TRE sequence is sufficient to confer TPA responsiveness to cells treated with TPA. Gel retardation assays and DNA footprint analysis demonstrated specific binding of the TRE and protection of the TRE sequence. Thus, these results describe a TRE in the 5'-flanking region of the AR gene and demonstrate that the TRE is responsive to TPA treatment.
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PMID:Characterization of a TPA-response element in the 5'-flanking region of the androgen receptor gene. 979 20

The possibility that Sertoli cell responses to testosterone are modulated by the calcium/phospholipid-dependent protein kinase (protein kinase C; PKC) was examined in rat Sertoli cells in culture. Both soluble and particulate cell fractions showed low constitutive phosphotransferase activity. Incubation with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA; 10(-7) M) was associated with a transient induction in both cell fractions of calcium/phosphatidylserine-dependent PKC activity, which was elevated from 15 min to 1 h. Consistent with this, mRNAs for the calcium/phospholipid-dependent isomeric forms of PKC (alpha, beta, and gamma) were detected. The expression levels of mRNAs for PKCalpha and PKCbeta were also up-regulated (2.5- to 3-fold) by TPA (10(-7) M), but these effects were much slower (peaking after 12 h) than those on phosphotransferase activity. In the presence of TPA (10(-7) M), expression of androgen receptor (AR) mRNA showed a transient time-dependent down-regulation ( approximately 70%), in which the nadir was reached after 6 h and baseline expression was again obtained after 12 h. The regulatory effect of PKC activation on AR mRNA was confirmed by the absence of response to a biologically inactive phorbol ester. A concentration-dependent decrease (half-maximal effect at approximately 10(-8) M TPA) of AR mRNA was also observed. These data suggest that Sertoli cell responses to testosterone may be inhibited by a transiently active PKC with a wide intracellular distribution.
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PMID:Calcium/phospholipid-dependent protein kinases in rat Sertoli cells: regulation of androgen receptor messenger ribonucleic acid. 1020 93

Androgens are important growth regulators in prostate cancer. Their known mode of action in target cells requires binding to a cytoplasmic androgen receptor followed by a nuclear translocation event and modulation of the expression of specific genes. Here, we report another mode of action of this receptor. Treatment of androgen responsive prostate cancer cells with dihydrotestosterone leads to a rapid and reversible activation of mitogen-activated protein kinases MAPKs (also called extracellular signal-regulated kinases or Erks). Transient transfection assays demonstrated that the androgen receptor-mediated activation of MAP kinase results in enhanced activity of the transcription factor Elk-1. This action of the androgen receptor differs from its known transcriptional activity since it is rapid and insensitive to androgen antagonists such as hydroxyflutamide or casodex. Biochemical studies as well as analyses with dominant negative mutants showed the involvement of kinases such as MAPK/Erk kinase, phosphatidyl-inositol 3-kinase and protein kinase C in the androgen receptor-mediated activation of MAP kinase. These results demonstrate a novel regulatory action of the androgen receptor and prove that in addition to its known transcriptional effects, it also uses non-conventional means to modulate several cellular signalling processes.
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PMID:Rapid signalling by androgen receptor in prostate cancer cells. 1059 31


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