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)

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

The plasma Sex Hormone-Binding Globulin (SHBG) transports androgens and estradiol in the blood and regulates their bioavailable fraction and access to target cells. The recent advances in the knowledge of its structure and gene expression, and notabily the demonstration of a specific receptor (SHBG-R) located on membranes of sex steroid responsive cells, gave support to the thesis that SHBG has much more sophisticated functions at cell site. In particular, the receptor-mediated action of SHBG, which uses as a second messenger cAMP, has been linked to the effects of androgens and estradiol. It is conceivable that the SHBG/SHBG-R system works as an additional control mechanism which inhibits or amplifies the effects of DHT and estradiol in cells. In the prostate, it has been suggested that the estradiol-activated SHBG/SHBG-R complex cross-talks with the androgen receptor, and is able to activate AR even in the absence of DHT. Of great interest, for its potential clinical applications, is the observation that in estrogen-dependent breast cancer SHBG, through SHBG-R, cAMP and PKA, specifically inhibits the estradiol-induction of cell proliferation. This anti-proliferative, anti-estrogenic effect of human SHBG has not only increased and continues to increase our understanding of the molecular mechanisms involved in the biology of breast cancer, but could also be exploited as a future therapeutic strategy in the managing of estrogen-dependent tumours.
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PMID:Sex hormone-binding globulin: not only a transport protein. What news is around the corner? 1021 93

Androgens are pivotal regulators of prostate cell growth, differentiation and function, and their actions are believed to be involved in prostate cancer development. The androgen-signaling pathway in the prostate gland is therefore one of the possible sites of intervention in prostate cancer prevention efforts. The central element of androgen signaling in the cell is the androgen receptor (AR), a member of the superfamily of nuclear receptors. Binding of androgen to its ligand-binding domain transforms the receptor to an active transcription factor that regulates gene expression by interacting with specific regulatory elements in the promoters of genes. In addition to this genomic action, the AR also interacts with other signaling pathways through protein-protein interaction, for example with AP-1 or Ets transcription factors. It is not only the action of androgenic hormones, but also the interactions with growth factor and protein kinase A-signaling pathways that can induce activation of AR. Moreover, these ligand-independent activators act synergistically together with low concentrations of androgens. The effects of long-term androgen deprivation on androgen signaling have been investigated in the LNCaP cell culture system. Long-term culture in a steroid-free medium results in a subline showing a hyperreactive AR characterized by increased AR expression and enhanced AR transcriptional activity in an environment with low levels of androgen hormones. It is not yet clear if similar changes also occur in normal or premalignant prostate epithelial cells and are thus relevant for prevention trials which interfere with androgen hormone signaling.
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PMID:Mechanism of androgen receptor activation and possible implications for chemoprevention trials. 1032 98

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.
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PMID:Prostate cancer: molecular biology of early progression to androgen independence. 1073 Sep 3

Regulatory control of the androgen receptor has been studied most extensively in prostatic tissue. Additional information has been obtained from the study of androgen receptors in pituitary and hypothalamic tissues, and these results can be extrapolated to regulatory mechanisms in both prostate and skeletal muscle. The present work provides a brief summary of studies on androgen action on muscle, gives an overview of mechanisms of androgen action on target tissues, and focuses on several aspects of regulation of androgen receptor (AR) gene expression. These include some characteristics of AR gene transcription start sites; the role of the cyclic adenosine monophosphate, protein kinase C, and protein kinase A pathways in mediating androgen receptor function; and tissue-variable regulatory elements inhibiting AR gene expression.
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PMID:Androgen receptors in prostate and skeletal muscle. 1095 12

Prostate cancer (PCA) is the most common invasive malignancy and leading cause (after lung) of cancer deaths in males. Since PCA is initially androgen-dependent, strategies are targeted toward androgen depletion for its control. However, tumor re-growth mostly occurs following this modality, and is androgen-independent. A loss of functional androgen receptor and an enhanced expression of growth factor receptors (e.g. erbB family members) and associated ligands have been shown to be the causal genetic events in PCA progression. These genetic alterations lead to an epigenetic mechanism where a feed-back autocrine loop between membrane receptor (e.g. epidermal growth factor receptor [erbB1] and associated ligand (e.g. transforming growth factor-alpha) results in an enhanced activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) as an essential component of the uncontrolled growth of PCA at an advanced and androgen-independent stage. Together, we rationalized that inhibiting these epigenetic events would be useful in controlling advanced PCA growth. Dietary polyphenolic flavonoids and isoflavones are being studied extensively as cancer-preventive and interventive agents. Therefore, we focused our attention on silymarin, genistein, and epigallocatechin 3-gallate (EGCG), present in milk thistle, soy beans, and green tea, respectively. The effect of these agents was assessed on the erbB1-Shc-ERK1/2 signal transduction pathway, cell cycle regulatory molecules, and cell growth and death. In androgen-independent human prostate carcinoma DU145 cells, silymarin, genistein, and EGCG resulted in a significant to complete inhibition of transforming growth factor-alpha-caused activation of membrane receptor erbB1 followed by inhibition of downstream cytoplasmic signaling target Shc activation and a decrease in its binding with erbB1, without an alteration in their protein expression. Silymarin and genistein also inhibited ERK1/2 activation, suggesting that these agents impair the activation of erbB1-Shc-ERK1/2 signaling in DU145 cells. In the case of EGCG, a further increase in ERK1/2 activation was observed that was related to its pro-oxidant and apoptotic activities. Silymarin, genistein, and EGCG also resulted in a significant induction of Cip1/p21 and Kip1/p27 and a decrease in cyclin-dependent kinase (CDK) 4, but a moderate inhibition of CDK2, cyclin D1, and cyclin E was observed. An enhanced level of Cip1/p21 and Kip1/27 also led to an increase in their binding to CDK4 and CDK2. Treatment of cells with silymarin, genistein, and EGCG also resulted in strong cell growth inhibition at lower doses, and complete inhibition at higher doses. In contrast to silymarin, higher doses of genistein also showed cell death. A more profound cytotoxic effect was observed in the case of EGCG, with strong cell death at lower doses and complete loss of viability at higher doses. Together, these results suggest that cell signaling and regulators of cell cycle are potential epigenetic molecular targets for prostate cancer prevention by dietary agents. More studies, therefore, are needed with these agents to explore their anticarcinogenic potential against human prostate cancer.
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PMID:Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents. 1100 41

Treatment of human prostate carcinoma-derived LNCaP cells with androgen or oestradiol triggers simultaneous association of androgen receptor and oestradiol receptor beta with Src, activates the Src/Raf-1/Erk-2 pathway and stimulates cell proliferation. Surprisingly, either androgen or oestradiol action on each of these steps is inhibited by both anti-androgens and anti-oestrogens. Similar findings for oestradiol receptor alpha were observed in MCF-7 or T47D cells stimulated by either oestradiol or androgens. Microinjection of LNCaP, MCF-7 and T47D cells with SrcK(-) abolishes steroid-stimulated S-phase entry. Data from transfected Cos cells confirm and extend the findings from these cells. Hormone-stimulated Src interaction with the androgen receptor and oestradiol receptor alpha or beta is detected using glutathione S:-transferase fusion constructs. Src SH2 interacts with phosphotyrosine 537 of oestradiol receptor alpha and the Src SH3 domain with a proline-rich stretch of the androgen receptor. The role of this phosphotyrosine is stressed by its requirement for association of oestradiol receptor alpha with Src and consequent activation of Src in intact Cos cells.
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PMID:Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation. 1103 8

This article reviews recent findings on androgen receptor expression, structure, and function in carcinoma of the prostate. In this decade, it became clear that androgen-resistant prostate cancers contain androgen receptors and, therefore, regulation of androgen receptor expression and function receives considerable attention. The article summarizes findings on regulation of androgen receptor expression by androgens, growth factors, and protein kinase A activators. In addition, modulation of function of the wild-type and mutant AR is discussed. Androgen receptor functional activity is up-regulated by androgens and nonsteroidal activators, which influence transcription of androgen receptor-regulated genes in a cell type-dependent manner. This study also contains a chapter on androgen receptor-associated proteins, coactivators, and coreppressors and their possible role in pathological situations.
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PMID:Expression and function of androgen receptor in carcinoma of the prostate. 1107 15

The early demonstrations that prostate cancer was hormone-sensitive initiated a therapeutic strategy of hormone ablation that is still in use today. Although chemical or surgical castration reduces androgen stimulation of the androgen receptor (AR) and produces tumor regression, little survival benefit is achieved. Patients with metastatic cancer eventually relapse as their tumors progress to hormone independence. The AR is a member of the steroid receptor family; however, it manifests many unique features including: N-terminal, C-terminal interactions and antiparallel dimerization, unique N-terminal domains for co-factor recruitment, AR-specific co-activators and upstream promoter/enhancer response elements that amplify AR-mediated responses. The AR is regulated by phosphorylation and cross-talk with several signaling pathways, including MAP kinases, PKA and PKC. Non-genomic effects of AR to regulate transcription factors elk-1 and -2 have also been demonstrated. These unique features suggest mechanisms by which novel therapeutics might target and influence AR-mediated actions. Progress in this direction has been realized with the recent synthesis of non-steroidal androgen agonists that may have tissue-selective effects.
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PMID:Prostate cancer and the androgen receptor: strategies for the development of novel therapeutics. 1112 64

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.
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PMID:Interleukin-6 induces androgen responsiveness in prostate cancer cells through up-regulation of androgen receptor expression. 1141 May 19


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