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 intracellular effector oligonucleotides ppp(A2'p)nA (n = 2- greater than or equal to 4) regulate the breakdown of RNA by activating ppp(A2'p)nA-dependent RNase. Cellular levels of this RNase were demonstrated to be regulated during differentiation of murine embryonal carcinoma cells. An induction of this RNase by interferon was demonstrated in each of three differentiated cell types (F9 clone 9, PYS, and PSA 5E) by analyzing rRNA breakdown following the introduction of ppp(A2'p)nA into the intact cells. In contrast, in three undifferentiated embryonal carcinoma cell lines (F9, PC13 clone 5, and Nulli 2A) there was little if any ppp(A2'p)nA-dependent RNase either with or without interferon pretreatment. These results were confirmed by affinity labeling of the RNase in cell-free systems. Addition of the proteinase inhibitor, leupeptin, to the cell lysis buffer was necessary to stabilize the RNase against cleavage to discrete breakdown products. Moreover, during differentiation of PC13 clone 5 cells by retinoic acid and N6,O2'-dibutyryl-adenosine 3',5'-monophosphate there was a gradual induction of ppp(A2'p)nA-dependent RNase. The expression of this RNase is, therefore, greatly enhanced during cell differentiation. In addition, the double-stranded-RNA-dependent protein kinase was investigated and was found to be interferon-inducible in all of the cell lines regardless of the state of cell differentiation.
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PMID:Regulation of ppp(A2'p)nA-dependent RNase levels during interferon treatment and cell differentiation. 257 57

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

The up- and downregulation of polysialic acid-neural cell adhesion molecule (PSA-NCAM) expression on motorneurons during development is associated respectively with target innervation and synaptogenesis, and is regulated at the level of PSA enzymatic biosynthesis involving specific polysialyltransferase activity. The purpose of this study has been to describe the cellular mechanisms by which that regulation might occur. It has been found that developmental regulation of PSA synthesis by ciliary ganglion motorneurons is not reflected in the levels of polysialyltransferase-1 (PST) or sialyltransferase-X (STX) mRNA. On the other hand, PSA synthesis in both the ciliary ganglion and the developing tectum appears to be coupled to the concentration of calcium in intracellular compartments. This study documents a calcium dependence of polysialyltransferase activity in a cell-free assay over the range of 0.1-1 mM, and a rapid sensitivity of new PSA synthesis, as measured in a pulse-chase analysis of tissue explants, to calcium ionophore perturbation of intracellular calcium levels. Moreover, the relevant calcium pool appears to be within a specific intracellular compartment that is sensitive to thapsigargin and does not directly reflect the level of cytosolic calcium. Perturbation of other major second messenger systems, such as cAMP and protein kinase-dependent pathways, did not affect polysialylation in the pulse chase analysis. These results suggest that the shuttling of calcium to different pools within the cell can result in the rapid regulation of PSA synthesis in developing tissues.
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PMID:Regulation of neural cell adhesion molecule polysialylation: evidence for nontranscriptional control and sensitivity to an intracellular pool of calcium. 949 Jul 30

When androgen receptor containing cells are cultured in the presence of the PKA stimulator forskolin, a rapid dephosphorylation of the androgen receptor occurs resulting in a decrease in the amount of 112 kDa androgen receptor isoform and an increase in 110 kDa androgen receptor isoform on SDS-PAGE. To establish which amino acid residues in the androgen receptor were phosphorylated in control and forskolin-treated cells, trypsin-digested androgen receptors were subjected to RP-HPLC analysis and subsequently to Edman degradation. It was observed that serine residues 506, 641, and 653 were potentially phosphorylated in control cells, while after forskolin treatment strong evidence was obtained that phosphorylation of serines 641 and 653 was significantly reduced. When the dephosphorylated androgen receptor was analyzed for its transcription activation capacity, it was observed that androgen-induced transcriptional regulation of two endogenous genes (PSA) and beta 1-subunit of Na,K-ATPase), in cells cultured in the presence of forskolin, was inhibited as compared to the control situation. The observation that the dephosphorylated androgen receptor was transcriptionally less active was further strengthened by the finding that the dephosphorylated androgen receptor was markedly impaired in ligand binding (Bmax was found to be reduced by approximately 40%). The current investigations show for the first time a clear function for the rapid phosphorylation which occurs directly after synthesis of the androgen receptor, namely, effective ligand binding.
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PMID:Forskolin-induced dephosphorylation of the androgen receptor impairs ligand binding. 952 5

It has previously been shown that when boar spermatozoa are incubated in a modified Krebs-Ringer bicarbonate (mKRB), head-to-head agglutination occurs in many cells. The aim of the present study was to investigate the effects of cyclic adenosine 3',5'-monophosphate (cAMP) and serum albumin on sperm agglutination and to discuss a possible mechanism for sperm agglutination. Spermatozoa were collected from four mature boars, washed and incubated in mKRB. After a 1-h incubation, a sample of each sperm suspension was smeared gently on a separate glass slide, dried and stained in a phosphate-buffered solution of Giemsa to assess the percentage of head-to-head agglutinated cells in each suspension. In the samples incubated in mKRB, approximately 50% of the spermatozoa were agglutinated with one another at the acrosome. However, the percentages of head-to-head agglutinated spermatozoa were greatly reduced by a lack of calcium chloride in mKRB, but were recovered by the addition of dibutyryl cAMP (dbcAMP, a cAMP analogue) in a dose-dependent manner between 1 and 1000 microM. Addition of 3-isobutyl-1-methylxanthine (IBMX, 100 and 500 microM) instead of dbcAMP also significantly increased the percentages of head-to-head agglutinated spermatozoa. Moreover, the effects of adding dbcAMP were attenuated by treatment with Rp-adenosine 3',5'-cyclic monophosphorothioate triethylamine salt (0.25-1.0 mM, a cAMP antagonist) or H-89 (5 microM, a protein kinase-A inhibitor), but were enhanced by treatment with okadaic acid (500 nM) and calyculinA (500 nM) (inhibitors of protein serine/threonine phosphatase). In sperm samples incubated in mKRB containing 0.1% polyvinyl alcohol (mKRB-P) or mKRB-P lacking calcium chloride and supplemented with 1 mM dbcAMP, a lack of bovine serum albumin (BSA) resulted in a significant decrease in the percentages of head-to-head agglutinated spermatozoa. Addition of porcine serum albumin (PSA, 1-4 mg mL(-1)) or methyl-beta-cyclodextrin (MBC, 5-10 mg mL(-1)) instead of BSA was as effective as BSA (4 mg mL(-1)) in enhancing sperm agglutination. However, the effects of BSA (4 mg mL(-1)) or MBC (5 mg mL(-1)) were reduced by pre-mixing these reagents with cholesterol 3-sulfate (a cholesterol analogue, 5 microg mL(-1) for BSA and 375 microg mL(-1) for MBC). In addition, a protein 'anti-agglutinin' inhibiting sperm agglutination, was extracted from spermatozoa incubated with serum albumin or MBC and detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting techniques. The obtained Western blots revealed that sperm-bound anti-agglutinin was detected less in the samples incubated with either BSA (4 mg mL(-1)) or MBC (5-10 mg mL(-1)), compared with control samples. Moreover, pre-mixing MBC (5 mg mL(-1)) with cholesterol 3-sulfate (375 microg mL(-1)) reduced this reagent's effects on the loss of sperm-bound anti-agglutinin. Additionally, the assay of sperm agglutination and a chlortetracycline staining assay revealed that the percentages of head-to-head agglutinated spermatozoa were positively correlated with those of spermatozoa classified into B pattern (capacitated spermatozoa). These results are consistent with the following suggestions: (i) an adenylyl cyclase-cAMP-protein kinase system mediates a signalling pathway leading to head-to-head agglutination; and (ii) loss of anti-agglutinin from the spermatozoa may be modulated by changes in the plasma membrane induced by actions of serum albumin or MBC contained in a medium.
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PMID:Role of cyclic adenosine 3',5'-monophosphate and serum albumin in head-to-head agglutination of boar spermatozoa. 1145 Oct 22

To investigate whether the tumor suppressor gene PTEN affects the activity of the androgen receptor (AR), we monitored the expression of the apoptotic gene HA-Bax (inserted in an adenovirus where it is driven by the AR-responsive promoter ARR(2)PB) in the presence or absence of dihydrotestosterone, in PTEN (+) or (-) prostate cancer cell lines, infected with an adenovirus containing wild-type PTEN (Av-CMV-PTEN) or a control LacZ-expressing construct. Our results showed that AR transcriptional activity was antagonized by PTEN expression. This antagonism was not cell line dependent, as it was observed in both LNCaP and LAPC-4 cells, or promoter dependent, as it was observed for a reporter gene (HA-Bax) driven by an exogenous androgen-responsive promoter (the ARR(2)PB promoter), and for a native gene (prostate-specific antigen; PSA) driven by an endogenous AR-responsive promoter. Additional experiments performed with viruses containing constitutively active (Adeno-myrAkt) or dominant negative (Adeno-dnAkt) forms of Akt demonstrated that Akt, a protein kinase whose activation is known to be inhibited by PTEN, mediated the observed antagonism between PTEN and AR transcriptional activity. Recently, two putative Akt phosphorylation sites have been identified in the AR sequence. Site-directed mutagenesis was utilized to convert these two serine into alanine residues. The resulting construct, named CMV-AR S213A&S791A was transfected in AR (-) and PTEN (-) PC-3 cells in the presence or absence of Av-CMV-PTEN and of two reporter plasmids (GRE(2)E1b-Luc and PSA P/E-luc) containing the luciferase gene driven by well-characterized androgen responsive promoters. These experiments demonstrated that, similarly to the wild-type molecule, AR S213A&S791A was transcriptionally inhibited by PTEN, suggesting that Akt does not have an effect on AR transcription by direct phosphorylation, but probably by affecting the availability of a downstream molecule whose main mechanism of action is that of modulating AR transcription. The data presented here suggest that loss of PTEN function may facilitate activation of AR signaling and progression to androgen independence in prostate cancer.
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PMID:The PTEN tumor suppressor is a negative modulator of androgen receptor transcriptional activity. 1291 34

A cure for prostate cancer (CaP) will be possible only after a complete understanding of the mechanisms causing this disease to progress from androgen dependence to androgen independence. To carry on a careful characterization of the phenotypes of CaP cell lines before and after acquisition of androgen independence, we used two human CaP LNCaP sublines: LNCaP(nan), which is androgen dependent (AD), and LNCaP-HP, which is androgen independent (AI). In AD LNCaP(nan) cells, dihydrotestosterone (DHT) stimulated in an androgen receptor (AR)-dependent way a phosphorylation signaling pathway involving steroid receptor coactivator (Src)-mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)-1/2-ERK-1/2-cAMP-response element binding-protein (CREB). Activation of this pathway was associated with increased [(3)H]thymidine incorporation and resistance to apoptosis. Use of dominant-negative forms of MEK-1/2 and CREB demonstrated in LNCaP(nan) cells that DHT induced [(3)H]thymidiine incorporation through a thus far unidentified molecule activated downstream of MEK-1/2, and antiapoptosis through phosphorylation of the transcription factor CREB. In contrast, in AI LNCaP-HP cells, the Src-MEK-1/2-ERK-1/2-CREB pathway was constitutively active. Because it was not further stimulated by addition of DHT, no increase of [(3)H]thymidine incorporation or apoptosis resistance was demonstrated in LNCaP-HP cells. Additional experiments showed that Src and the scaffold protein MNAR coimmunoprecipitated with AR, indicating a role for Src as an apical molecule in the Src-MEK-1/2-ERK-1/2-CREB pathway. Interestingly, differences between the two cell lines were that in LNCaP-HP cells presence of an AI phenotype and lack of response to DHT were associated with constitutive activation of the protein kinase Src and interaction among Src, AR, and MNAR. In contrast, in LNCaP(nan) cells, presence of an AD phenotype and ability to respond to DHT were associated with DHT-dependent activation of Src kinase activity and interaction among Src, AR, and MNAR. Intriguingly, in LNCaP(nan) cells, we found that transcription through the prototypical CREB-responsive promoter c-fos could be induced in a DHT-dependent way, and this action was inhibited by the AR antagonist Casodex and MEK-1 inhibitor PD98059. In contrast, transcription through the PSA P/E promoter, a prototypical AR-dependent promoter directly activated by agonist, was obliterated only by Casodex. Additional experiments with genital skin fibroblasts derived from patients with a variety of AR abnormalities indicated that nongenotropic AR signaling does not depend on an intact DNA-binding domain or on the ability of AR to translocate to the nucleus. The results suggest the following: (1) Constitutive activation of the Src-MEK-1/2-ERK-1/2-CREB pathway is associated with the AI phenotype observed in LNCaP-HP cells. (2) Activation of the Src-MEK-1/2-ERK-1/2-CREB pathway is DHT dependent in AD LNCaP(nan) cells. (3) DHT activation of this pathway is associated with induction of [(3)H]thymidine incorporation by a molecule activated downstream of MEK-1/2 and of antiapoptosis through activation of the transcription factor CREB in AD LNCaP(nan) cells. (4) AR regulates transcription either directly upon ligand binding and nuclear translocation or indirectly through kinase pathways leading to activation of downstream transcription factors. (5) Nuclear translocation and ability of the DNA-binding domain of AR to interact with DNA are not prerequisites for nongenotropic AR activity.
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PMID:Changes in androgen receptor nongenotropic signaling correlate with transition of LNCaP cells to androgen independence. 1546 14

Resveratrol, trans-3,5,4'-trihydroxystilbene, was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes), but has since been found in various plants, including grapes, berries and peanuts. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP-1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down-regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL-8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer.
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PMID:Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 1551 85

Active metabolites of vitamin A and D are well known to act as growth inhibitors in hormone-related prostate and breast cancers. When various concentrations of 1alpha,25-dihydroxyvitamin D3 (vitamin D3), all-trans-retinoic acid (ATRA) and 9-cis retinoic acid (9-cis RA) were examined, the androgen-stimulated growth of mouse mammary carcinoma SC-3 cells was inhibited by vitamin D3 alone in a dose-dependent manner. A flow cytometer analysis showed that vitamin D3 leads SC-3 cells to relative G1-growth arrest after 72 h. Characterization of vitamin D3-responsive genes using an oligonucleotide microarray demonstrated that 220 genes were upregulated at more than threefold, and 84 genes were downregulated to less than one-third, compared with the testosterone-stimulated SC-3 cells. Neither cyclin-dependent kinase inhibitors (CDKIs) nor the antiapoptotic bcl-2 gene were induced in vitamin D3-responsive genes, with the exception of a slight induction of p15(INK4B). Importantly, fgf8 was markedly repressed in response to vitamin D3. The exogenous addition of FGF8 canceled the growth suppression by vitamin D3 in SC-3 cells, suggesting that the repression of fgf8 is an indispensable step in vitamin D3-mediated growth inhibition. In reporter assays using the ARE-containing artificial construct and the natural androgen-regulated PSA promoter, co-transfection of the vitamin D receptor (VDR) and androgen receptor (AR) suppressed AR-stimulated promoter activity. In addition, vitamin D3 also suppressed androgen-stimulated promoter activity in the stably transfected SC-3 cells. Moreover, VDR repressed the core promoter activity of fgf8 in COS1 cells and in the SC-3 cells. All these findings strongly suggest that vitamin D3 serves as a negative regulator for both androgen-related and fgf8 transcriptions.
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PMID:Vitamin D3 suppresses the androgen-stimulated growth of mouse mammary carcinoma SC-3 cells by transcriptional repression of fibroblast growth factor 8. 1650 48

Silymarin consists of a family of flavonoids (silybin, isosilybin, silychristin, silydianin and taxifoline) commonly found in the dried fruit of the milk thistle plant Silybum marianum. Although silymarin's role as an antioxidant and hepatoprotective agent is well known, its role as an anticancer agent has begun to emerge. Extensive research within the last decade has shown that silymarin can suppress the proliferation of a variety of tumor cells (e.g., prostate, breast, ovary, colon, lung, bladder); this is accomplished through cell cycle arrest at the G1/S-phase, induction of cyclin-dependent kinase inhibitors (such as p15, p21 and p27), down-regulation of anti-apoptotic gene products (e.g., Bcl-2 and Bcl-xL), inhibition of cell-survival kinases (AKT, PKC and MAPK) and inhibition of inflammatory transcription factors (e.g., NF-kappaB). Silymarin can also down-regulate gene products involved in the proliferation of tumor cells (cyclin D1, EGFR, COX-2, TGF-beta, IGF-IR), invasion (MMP-9), angiogenesis (VEGF) and metastasis (adhesion molecules). The antiinflammatory effects of silymarin are mediated through suppression of NF-kappaB-regulated gene products, including COX-2, LOX, inducible iNOS, TNF and IL-1. Numerous studies have indicated that silymarin is a chemopreventive agent in vivo against a variety of carcinogens/tumor promoters, including UV light, 7,12-dimethylbenz(a)anthracene (DMBA), phorbol 12-myristate 13-acetate (PMA) and others. Silymarin has also been shown to sensitize tumors to chemotherapeutic agents through down-regulation of the MDR protein and other mechanisms. It binds to both estrogen and androgen receptors, and down-regulates PSA. In addition to its chemopreventive effects, silymarin exhibits antitumor activity against human tumors (e.g., prostate and ovary) in rodents. Various clinical trials have indicated that silymarin is bioavailable and pharmacologically safe. Studies are now in progress to demonstrate the clinical efficacy of silymarin against various cancers.
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PMID:Anticancer potential of silymarin: from bench to bed side. 1720 Nov 69


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