Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 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

The effect of androgen on intranuclear distribution of androgen receptor binding sites was studied. The level of the androgen receptor complex in dinucleosomes increased 1 h after androgen treatment and those in the mono- and trinucleosomes increased 3 h after androgen treatment. Investigation by 32P incorporation into the nuclei and active chromatin showed that androgen resulted in an increase in the rate of phosphorylation at 3 h and reduced to the control level at 6 h. These data suggest that association of androgen receptor with the acceptor sites and activities of protein kinase in active chromatin are simultaneously stimulated for activating the transcription by androgen.
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PMID:Effects of androgen on phosphorylation of chromosomal proteins in mouse submandibular gland. 161 Mar 85

The androgen receptor was purified from rat ventral prostate. The purified receptor migrated as a single band of mol. wt. 87000 on SDS-polyacrylamide gels, had a kd for R-1881 (17 beta-hydroxy-17 alpha-methyl-estra-4,9,11-trien-3-one) binding as 6 nM, and sedimentation coefficient of 4.5 S. Phosphorylation of the purified receptor was studied by incubating it with [gamma-32P]ATP in the presence of several purified protein kinases including cAMP-dependent protein kinase, and four cAMP-independent protein kinases (which were active towards substrates such as phosvitin and casein). Phosphorylation of the 87000 mol. wt. androgen receptor protein occurred only in the presence of a nuclear cAMP-independent protein kinase (of the N2 type). No auto-phosphorylation of the receptor was detected. The results indicate that the androgen receptor is a phosphoprotein. Further, phosphorylation of the androgen receptor by only a specific nuclear cAMP-independent protein kinase may be important in determining the dynamics of its function.
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PMID:Phosphorylation of the androgen receptor by a nuclear cAMP-independent protein kinase. 609 41

Nuclear matrix fraction was isolated from rat ventral prostatic nuclei previously incubated with [gamma-32P]ATP to label nuclear phosphoproteins with 32P. A significant portion of the radioactivity was recovered in the phosphoproteins intrinsic to the nuclear matrix fraction. At 12 h after androgen deprivation (i.e., when a significant portion of the nuclear androgen receptor was known to be depleted), the rate, but not the extent, of phosphorylation of nuclear proteins (predominantly nonhistone proteins) was markedly reduced. Nuclear matrix fraction isolated from such preparations demonstrated a profound reduction in the rate of incorporation of 32P into the matrix-associated proteins without any apparent change in the gel electrophoretic profile of these proteins. The results indicate that the cAMP-independent protein kinase activity which catalyzes the phosphorylation of nuclear matrix proteins is under androgenic control. This may be germane to nuclear matrix-associated initial events in androgen action.
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PMID:Phosphorylation of prostatic nuclear matrix proteins is under androgenic control. 649 89

Androgens stringently regulate the concentrations of the polyamines, spermine and spermidine, in rat ventral prostate. The intracellular distribution of the polyamines is also dependent on the androgenic milieu; a small proportion of polyamines is associated tightly with the nucleus. Soluble nucleolar chromatin contains RNA polymerase A and protein kinase activities, both of which are regulated by androgens and markedly stimulated by polyamines. It remains to be established whether the polyamines modulate these enzyme moieties directly, or whether the phosphorylation of other nucleolar proteins plays a crucial role in the androgenic regulation of rRNA synthesis. Using a protocol centered on affinity chromatography, the purification of the androgen receptor protein to a state approaching homogeneity has been accomplished. The purified receptor stimulates the RNA polymerase A and protein kinase activities associated with prostate nucleolar chromatin. The significance of these findings in the light of correct concepts of steroid hormone action is discussed.
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PMID:Enhanced transcription of rRNA genes by purified androgen receptor complexes in vitro. 688 53

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

In our studies of protein kinase CK2, or casein kinase 2, we have focused on its regulation in relation to altered genomic activity in response to androgen action (through the function of the androgen receptor) in the male accessory sex gland, the prostate. We have documented that androgens exert a profound effect on CK2 in the prostate. Investigation of androgenic regulation of the molecular expression of prostatic CK2 suggested that CK2 gene transcription, although substantial in the prereplicative phase of cell proliferation, is not an early event in androgen action. The lack of rapid transcriptional regulation of CK2 by androgens suggested an alternative mechanism for our original observations on the early regulation of CK2-mediated reactions. A rigorous analysis of the CK2 in different compartments of the prostatic cell has suggested its differential regulation. For example, androgen withdrawal results in a rapid loss of CK2 protein and activity in the prostatic cell nucleus, whereas the activity and protein in the cytosol undergoes a slow decline over several days. A single dose of 5 alpha-dihydrotestosterone (5 alpha-DHT) given to 6-d castrated animals results in an increase in nuclear enzymatic activity as well as immunoreactive CK2 protein within 1 h, while a concomitant decrease is apparent in the cytosolic fraction. Within the nucleus, there appears to be a differential androgenic regulation of CK2 such that the enzyme associated with chromatin and nuclear matrix (NM) demonstrates a substantially greater androgen sensitivity than the enzyme in the nucleoplasm.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of intracellular regulation of protein kinase CK2: role of stimulus-mediated subnuclear association. 773 28

The effect of modulators of protein phosphorylation on the transcriptional activity of the androgen receptor (AR) was studied under transient expression conditions. Activators of protein kinase-A [8-bromo-cAMP (8-Br-cAMP)] and protein kinase-C (phorbol 12-myristate 13-acetate) or an inhibitor of protein phosphatase-1 and -2A (okadaic acid) influenced minimally pMMTV-chloramphenicol acetyl-transferase (CAT) activity in CV-1 cells cotransfected with an AR expression plasmid in the absence of androgen. In the presence of testosterone, however, all compounds enhanced AR-mediated transactivation by 2- to 4-fold. A nonsteroidal antiandrogen, Casodex, behaved as a pure antagonist; it blunted the action of testosterone and was not rendered agonistic by activators of protein kinase-A. A reporter plasmid containing two androgen response elements (AREs) in front of the thymidine kinase promoter (pARE2tk-CAT) was also used to examine promoter specificity. It was activated by 8-Br-cAMP, forskolin, or okadaic acid even without AR or androgen. However, when forskolin or okadaic acid was used together with androgen and AR, the resulting AR-dependent transactivation of pARE2tk-CAT was more than additive. Intact DNA- and ligand-binding domains, but not the N-terminal amino acid residues 40-147, of the receptor were mandatory for the synergism between protein kinase-A activators and androgen. Immunoreactive AR content in transfected COS-1 cells was not influenced by exposure to 8-Br-cAMP. Similar results were obtained by ligand binding assays. Quantitative or qualitative differences were not observed in DNA-binding characteristics between receptors extracted from cells treated with testosterone with or without protein kinase-A activator. Collectively, the synergistic stimulation of AR-dependent transactivation by androgen and protein kinase activators is not due to changes in cellular AR content or affinity of the receptor for the cognate DNA element; rather, this phenomenon seems to result from altered interaction of ligand-activated AR with other proteins in the transcription machinery.
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PMID:Stimulation of androgen-regulated transactivation by modulators of protein phosphorylation. 792 97

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.
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PMID:Activation of the androgen receptor by polypeptide growth factors and cellular regulators. 858 Sep 99

Aberrant activation of the androgen receptor through signaling pathways independent of androgen may be responsible for the progression of prostate tumors to the rapidly proliferating androgen-independent state. In this study, the effects of protein kinase A modulators on human androgen receptor activity were tested. Using an adenoviral DNA delivery system, we demonstrate that the androgen receptor can be activated by a protein kinase A activator, forskolin, in the absence of androgen when androgen receptor is co-transfected into monkey kidney CV1 cells or human prostate PC-3 cells with androgen-responsive reporters. Immunoblotting reveals that there is no significant change in androgen receptor protein level following forskolin treatment, suggesting that the enhanced activity is due to activation of the receptor. This activation can be blocked by a protein kinase A inhibitor peptide. Two potent anti-androgens, casodex and flutamide, can significantly reduce this activation, confirming that the ligand-independent pathway is an androgen receptor-mediated phenomenon. An intact DNA binding domain of the receptor is critical for this alternate signaling pathway since mutants with reduced DNA binding ability are inactive. The phosphorylation status of the androgen receptor or associated proteins may critically modulate receptor activity and should be considered when designing improved approaches to prostate cancer therapy.
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PMID:Activation of the human androgen receptor through a protein kinase A signaling pathway. 870 3


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