Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of transcription factors that respond to specific ligands by altering gene expression in a cell-, developmental- and sex-specific manner. Three subtypes of this receptor have been discovered (PPARalpha, beta and gamma), each apparently evolving to fulfill different biological niches. PPARs control a variety of target genes involved in lipid homeostasis, diabetes and cancer. Similar to other nuclear receptors, the PPARs are phosphoproteins and their transcriptional activity is affected by cross-talk with kinases and phosphatases. Phosphorylation by the mitogen-activated protein kinases (ERK- and p38-MAPK), Protein Kinase A and C (PKA, PKC), AMP Kinase (AMPK) and glycogen synthase kinase-3 (GSK3) affect their activity in a ligand-dependent or -independent manner. The effects of phosphorylation depend on the cellular context, receptor subtype and residue metabolized which can be manifested at several steps in the PPAR activation sequence including ligand affinity, DNA binding, coactivator recruitment and proteasomal degradation. The review will summarize the known PPAR kinases that directly act on these receptors, the sites affected and the result of this modification on receptor activity.
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PMID:Modulation of PPAR activity via phosphorylation. 1756 Aug 26

The basal transcriptional activity of nuclear receptors (NRs) is regulated by interactions with additional comodulator proteins (coactivator/corepressor). Here, we describe a new androgen receptor (AR)-associated coactivator, PRMT2, which belongs to the arginine methyltransferase protein family. To search for AR-interacting proteins a fragment of the AR was used in a library screen exploiting the yeast two-hybrid technique and identifying the C-terminal region of PRMT2. We demonstrated that PRMT2 acts as a strong coactivator of the AR, had modest or none influence on transcriptional activation mediated by other NRs. Interestingly, PRMT2 interaction with the estrogen receptor (ER) was strongly dependent on the cellular background, thus, suggesting the involvement of additional, differentially expressed coregulators. We also demonstrated synergistic interaction of PRMT2 with other known nuclear receptor coactivators, such as GRIP1/TIF-2. Potentiation of AR-mediated transactivation by PRMT2 alone and in synergism with GRIP1 was prevented by a competitive inhibitor of methyltransferase activity. The PRMT2 expression profile overlaps with the distribution of AR, with strongest PRMT2 abundance in androgen target tissues. Immunofluorescence experiments showed that the intracellular localization of PRMT2 depends on the presence of the cognate receptor ligand. Under androgen-free conditions, both AR and PRMT2 are confined to the cytoplasm, whereas in the presence of androgens both proteins colocalize and translocate into the nucleus. Treatment with the AR antagonist hydroxyflutamide results in nuclear translocation of the AR, but not the coactivator PRMT2. Thus, it appears that the ligand-dependent AR conformation is essential for the recruitment and nuclear translocation of PMRT2 which acts as AR-coactivator, presumably by arginine methylation.
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PMID:PRMT2, a member of the protein arginine methyltransferase family, is a coactivator of the androgen receptor. 1758 66

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a ligand-activated transcription factor of the nuclear receptor superfamily that regulates genes involved in differentiation, metabolism and immunity. PPARgamma-ligands are used for therapy of type 2 diabetes and hold the promise for treatment of inflammation and cancer. As a central regulatory component, PPARgamma activity is well regulated during various cellular processes, and indeed mitogenic stimulation often suppresses PPARgamma's genomic activity. This downregulation is mediated largely by the extracellular signal-regulated kinase 1/2 (ERKs)/mitogen-activated protein kinases (MAPKs) signaling cascade, which attenuates PPARgamma's transactivation function either by an inhibitory phosphorylation or by modulating PPARgamma's nucleo-cytoplasmic compartmentalization. The latter is achieved by the mitogen-induced nuclear export of PPARgamma through its direct interaction with the ERK cascade component MAPK/ERK-kinases 1/2 (MEKs). Upon mitogenic stimulation, MEKs translocate into the nucleus, but are rapidly exported from this location by their N-terminal nuclear export signal (NES), in a process that is accompanied by the export of their interacting nuclear PPARgamma molecules. Interestingly, it was recently demonstrated that PPARgamma has cytoplasmatic activities, and therefore, the MEK-dependent shuttle may also represent a mechanism for control of the extra-nuclear/nongenomic actions of PPARgamma. Because of the similarity within nuclear receptor docking motifs, it is possible that the same mechanism may control the nuclear and cytoplasmatic activity of other receptors. The changes in the subcellular localization of PPARgamma may also represent novel targets for selective interference in patients with chronic inflammatory or proliferation-related diseases.
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PMID:MAPK kinases as nucleo-cytoplasmic shuttles for PPARgamma. 1761 13

Steroid hormones exert profound effects on cell growth, development, differentiation, and homeostasis. Their effects are mediated through specific intracellular steroid receptors that act via multiple mechanisms. Among others, the action mechanism starting upon 17beta-estradiol (E2) binds to its receptors (ER) is considered a paradigmatic example of how steroid hormones function. Ligand-activated ER dimerizes and translocates in the nucleus where it recognizes specific hormone response elements located in or near promoter DNA regions of target genes. Behind the classical genomic mechanism shared with other steroid hormones, E2 also modulates gene expression by a second indirect mechanism that involves the interaction of ER with other transcription factors which, in turn, bind their cognate DNA elements. In this case, ER modulates the activities of transcription factors such as the activator protein (AP)-1, nuclear factor-kappaB (NF-kappaB) and stimulating protein-1 (Sp-1), by stabilizing DNA-protein complexes and/or recruiting co-activators. In addition, E2 binding to ER may also exert rapid actions that start with the activation of a variety of signal transduction pathways (e.g. ERK/MAPK, p38/MAPK, PI3K/AKT, PLC/PKC). The debate about the contribution of different ER-mediated signaling pathways to coordinate the expression of specific sets of genes is still open. This review will focus on the recent knowledge about the mechanism by which ERs regulate the expression of target genes and the emerging field of integration of membrane and nuclear receptor signaling, giving examples of the ways by which the genomic and non-genomic actions of ERs on target genes converge.
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PMID:Estrogen signaling multiple pathways to impact gene transcription. 1836 6

The peroxisome proliferator-activated receptor alpha (PPARalpha) belongs to the nuclear receptor family and plays a central role in the regulation of lipid metabolism, glucose homeostasis and inflammatory processes. In addition to its ligand-induced activation, PPARalpha is regulated by phosphorylation via ERK-MAPK, PKA and PKC. In this study we examined the effect of p38-MAPK on PPARalpha transcriptional activity. In COS-7 cells, anisomycin, a p38 activator, induced a dose-dependent phosphorylation of PPARalpha and a 50% inhibition of its transcriptional activity. In H4IIE hepatoma cells, anisomycin-induced p38 phosphorylation decreased both endogenous and PPARalpha ligand-enhanced L-CPTI and ACO gene expression. Interestingly, PPARalpha/p38 interaction required the molecular adapter ZIP/p62. Reducing ZIP/p62 expression by siRNA, partially reversed the inhibitory effect of anisomycin on L-CPTI gene expression. In conclusion, we showed that p38 activation induced PPARalpha phosphorylation and inhibition of its transcriptional activity through a trimeric interaction between p38-MAPK, ZIP/p62 and PPARalpha.
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PMID:Involvement of ZIP/p62 in the regulation of PPARalpha transcriptional activity by p38-MAPK. 1837 65

PELP1 (proline-, glutamic acid-, and leucine-rich protein-1) is a novel estrogen receptor (ER)-interacting protein that has been implicated to be important for mediation of both the genomic and nongenomic signaling of 17beta-estradiol (E2). PELP1 contains ten nuclear receptor-interacting boxes (LXXLL motifs), which allow it to interact with ER and other nuclear hormone receptors, a zinc finger, a glutamic acid-rich domain, and two proline-rich domains. The proline-rich regions contain several consensus PXXP motifs, which allow PELP1 to couple the ER with SH3 domain-containing kinase signaling proteins, such as Src and PI3K P85 regulatory subunit. PELP1 is expressed in many different brain regions, including the hippocampus, hypothalamus, and cerebral cortex. Further work has demonstrated that PELP1 is colocalized with ER-alpha in neurons in various brain regions. PELP1 is primarily expressed in neurons, with some expression also observed in glia. Subcellular localization studies revealed that PELP1 is highly localized in the cell nucleus of neurons, with some cytoplasm localization as well, and PELP1 is also localized at synaptic sites. Work in other tissues has demonstrated that PELP1 is critical for nongenomic and genomic signaling by E2, as PELP1 knockdown studies significantly attenuates E2-induced activation of ERK and Akt signaling pathways, and inhibits E2 genomic transcriptional effects on gene expression in breast cancer cells. Preliminary studies in the brain, suggests that similar roles may exist for PELP1 in the brain, but this remains to be established, and further work to characterize the precise roles and functions of PELP1 in the brain are needed.
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PMID:PELP1--a novel estrogen receptor-interacting protein. 1857 32

Deprivation of estrogen causes breast tumors in women to adapt and develop enhanced sensitivity to this steroid. Accordingly, women relapsing after treatment with oophorectomy, which substantially lowers estradiol for a prolonged period, respond secondarily to aromatase inhibitors with tumor regression. We have utilized in vitro and in vivo model systems to examine the biologic processes whereby Long Term Estradiol Deprivation (LTED) causes cells to adapt and develop hypersensitivity to estradiol. Several mechanisms are associated with this response including up-regulation of ERalpha and the MAP kinase, PI-3-kinase and mTOR growth factor pathways. ERalpha is 4-10 fold up-regulated as a result of demethylation of its C promoter, This nuclear receptor then co-opts a classical growth factor pathway using SHC, Grb-2 and Sos. This induces rapid nongenomic effects which are enhanced in LTED cells. The molecules involved in the nongenomic signaling process have been identified. Estradiol binds to cell membrane-associated ERalpha which physically associates with the adaptor protein SHC and induces its phosphorylation. In turn, SHC binds Grb-2 and Sos which results in the rapid activation of MAP kinase. These nongenomic effects ofestradiol produce biologic effects as evidenced by Elk-1 activation and by morphologic changes in cell membranes. Additional effects include activation of the PI-3-kinase and mTOR pathways through estradiol-induced binding of ERalpha to the IGF-1 and EGF receptors. A major question is how ERalpha locates in the plasma membrane since it does not contain an inherent membrane localization signal. We have provided evidence that the IGF-1 receptor serves as an anchor for ERalpha in the plasma membrane. Estradiol causes phosphorylation of the adaptor protein, SHC and the IGF-1 receptor itself. SHC, after binding to ERalpha, serves as the "glue" which tethers ERalpha to SHC binding sites on the activated IFG-1 receptors. Use of siRNA methodology to knock down SHC allows the conclusion that SHC is needed for ERalpha to localize in the plasma membrane. In order to abrogate growth factor induced hypersensitivity, we have utilized a drug, farnesylthiosalicylic acid, which blocks the binding of GTP-Ras to its membrane acceptor protein, galectin 1 and reduces the activation of MAP kinase. We have shown that this drug is a potent inhibitor of mTOR and this provides the major means for inhibition of cell proliferation. The concept of "adaptive hypersensitivity" and the mechanisms responsible for this phenomenon have important clinical implications. The efficacy ofaromatase inhibitors in patients relapsing on tamoxifen could be explained by this mechanism and inhibitors of growth factor pathways should reverse the hypersensitivity phenomenon and result in prolongation of the efficacy of hormonal therapy for breast cancer.
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PMID:Adaptation to estradiol deprivation causes up-regulation of growth factor pathways and hypersensitivity to estradiol in breast cancer cells. 1863 82

The nuclear receptor PPARgamma is a lipid sensor that regulates lipid metabolism through gene transcription. Inhibition of PPARgamma activity by TNF-alpha is involved in pathogenesis of insulin resistance, atherosclerosis, inflammation, and cancer cachexia. PPARgamma activity is regulated by TNF-alpha at pre-translational and post-translational levels. Activation of serine kinases including IKK, ERK, JNK, and p38 may be involved in the TNF-regulation of PPARgamma. Of the four kinases, IKK is a dominant signaling molecule in the TNF-regulation of PPARgamma. IKK acts through at least two mechanisms: inhibition of PPARgamma expression and activation of PPARgamma corepressor. In this review article, literature is reviewed with a focus on the mechanisms of PPARgamma inhibition by TNF-alpha.
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PMID:Regulation of PPARgamma function by TNF-alpha. 1865 73

ERBB2 overexpression in estrogen receptor (ER)-positive breast cancer cells such as BT474 (BT) cells has been found to confer resistance to tamoxifen, and suppression of ERBB2 improves the antiproliferative effects of tamoxifen. In this study, the responsiveness to tamoxifen in the BT/HerR, Herceptin-resistant BT cell lines established through constant Herceptin exposure, was evaluated. Compared with BT cells, improvement of sensitivity to tamoxifen in BT/HerR was demonstrated by ER functional analysis and cell proliferation assay. Tamoxifen in the resistant cell line was found to inhibit 17beta-estradiol-stimulating estrogen-responsive gene pS2 expression more effectively than in BT cells in real-time PCR assay. Western blot analysis showed that cross-phosphorylation between ER and downstream components of ERBB2 was attenuated in BT/HerR cells. ER redistribution from cytoplasm to nucleus could be found in these cells through immunofluorescence and confocal studies, and importantly, chromatin immunoprecipitation studies demonstrated that tamoxifen induced occupancy of the pS2 promoter by ER and nuclear receptor corepressor (NCOR1) instead of coactivator NCOA3 in these cells. Finally, combination of tamoxifen and Herceptin was found to improve the sensitivity of BT/HerR cells to Herceptin. Our results suggest that the ER genomic pathway in the ER-positive and Herceptin-resistant breast cancer cells may be reactivated, allowing tamoxifen therapy to be effective again, and a combination of tamoxifen and Herceptin can be a potential therapeutic strategy for ER-positive and Herceptin-resistant human breast cancer.
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PMID:Improvement of sensitivity to tamoxifen in estrogen receptor-positive and Herceptin-resistant breast cancer cells. 1876 63

The protein kinase C (PKC) signaling pathway plays integral roles in the expression of the steroidogenic acute regulatory (StAR) protein that regulates steroid biosynthesis in steroidogenic cells. PKC can modulate the activity of cAMP/protein kinase A signaling involved in steroidogenesis; however, its mechanism remains obscure. In the present study, we demonstrate that activation of the PKC pathway, by phorbol 12-myristate 13-acetate (PMA), was capable of potentiating dibutyryl cAMP [(Bu)(2)cAMP]-stimulated StAR expression, StAR phosphorylation, and progesterone synthesis in both mouse Leydig (MA-10) and granulosa (KK-1) tumor cells. The steroidogenic potential of PMA and (Bu)(2)cAMP was linked with phosphorylation of ERK 1/2; however, inhibition of the latter demonstrated varying effects on steroidogenesis. Transcriptional activation of the StAR gene by PMA and (Bu)(2)cAMP was influenced by several factors, its up-regulation being dependent on phosphorylation of the cAMP response element binding protein (CREB). An oligonucleotide probe containing a CREB/activating transcription factor binding region in the StAR promoter was found to bind nuclear proteins in PMA and (Bu)(2)cAMP-treated MA-10 and KK-1 cells. Chromatin immunoprecipitation studies revealed that the induction of phosphorylated CREB was tightly correlated with in vivo protein-DNA interactions and recruitment of CREB binding protein to the StAR promoter. Ectopic expression of CREB binding protein enhanced CREB-mediated transcription of the StAR gene, an event that was markedly repressed by the adenovirus E1A oncoprotein. Further studies demonstrated that the activation of StAR expression and steroid synthesis by PMA and (Bu)(2)cAMP was associated with expression of the nuclear receptor Nur77, indicating its essential role in hormone-regulated steroidogenesis. Collectively, these findings provide insight into the mechanisms by which PKC modulates cAMP/protein kinase A responsiveness involved in regulating the steroidogenic response in mouse gonadal cells.
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PMID:Mechanisms of protein kinase C signaling in the modulation of 3',5'-cyclic adenosine monophosphate-mediated steroidogenesis in mouse gonadal cells. 1928 84


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