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)

Neuroblastoma (NB) is the most common solid pediatric tumor. IMR-32 cells are a highly malignant human NB cell line with uncontrolled proliferation but with the potential to be differentiated under specific conditions. Preliminary research indicated that connexin 43 (Cx43), the most widespread of the Cx family, is aberrantly located in IMR-32 cells, which renders these cells incapable of gap junction (GJ) intercellular communication. Functioning GJ intercellular communication has been strongly associated with growth control and a decrease in tumorigenicity. 8-br-cAMP, known to initiate the differentiation process in cancer cells, was used to examine changes in Cx43 localization and expression via immunocytochemistry, Western blot analysis, and flow cytometry. Exposure of IMR-32 cells to 8-br-cAMP decreased cell proliferation, restored the abnormally localized Cx43 from around the nucleus to the cell membrane, increased de novo Cx43 protein expression, and appeared to phosphorylate Cx43 on serine (Ser) 255 and Ser262. Forskolin, an activator of cAMP dependent protein kinase (PKA), produced identical results to 8-br-cAMP demonstrating the effect that was not unique to a cAMP analog. The use of a PKA inhibitor further confirmed the specificity of 8-br-cAMP and forskolin's effect on Cx43. The cellular relocation of Cx43, combined with the increased protein expression, established first ever GJ intercellular communication between IMR-32 cells as revealed by scrape loading. These results suggest that the GJ-mediated return of growth control, as a prerequisite for further differentiation, offers a new therapeutic avenue in the treatment of NB.
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PMID:Cellular sublocalization of Cx43 and the establishment of functional coupling in IMR-32 neuroblastoma cells. 1560 63

A preliminary expression profiling analysis of osteoblasts derived from tibia explants of the high bone mass LRP5 G171V transgenic mice demonstrated increased expression of canonical Wnt pathway and Wnt/beta-catenin target genes compared with non-transgenic explant derived osteoblasts. Therefore, expression of Wnt/beta-catenin target genes were monitored after in vivo loading of the tibia of LRP5 G171V transgenic mice compared with non-transgenic mice. Loading resulted in the increased expression of Wnt pathway and Wnt/beta-catenin target genes including Wnt10B, SFRP1, cyclin D1, FzD2, WISP2, and connexin 43 in both genotypes; however, there was a further increased in transcriptional response with the LRP5 G171V transgenic mice. Similar increases in the expression of these genes (except cyclin D1) were observed when non-transgenic mice were pharmacologically treated with a canonical Wnt pathway activator, glycogen synthase kinase 3beta inhibitor and then subjected to load. These in vivo results were further corroborated by in vitro mechanical loading experiments in which MC3T3-E1 osteoblastic cells were subjected to 3400 microstrain alone for 5 h, which increased the expression of Wnt10B, SFRP1, cyclin D1, FzD2, WISP2, and connexin 43. Furthermore, when MC3T3-E1 cells were treated with either glycogen synthase kinase 3beta inhibitor or Wnt3A to activate Wnt signaling and then subjected to load, a synergistic up-regulation of these genes was observed compared with vehicle-treated cells. Collectively, the in vivo and in vitro mechanical loading results support that Wnt/beta-catenin signaling is a normal physiological response to load and that activation of the Wnt/beta-catenin pathway enhances the sensitivity of osteoblasts/osteocytes to mechanical loading.
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PMID:Wnt/beta-catenin signaling is a normal physiological response to mechanical loading in bone. 1690 22

In recent years, mammalian oocytes have been proposed to have important roles in the orchestration of ovarian follicular development and fertility. To determine whether intra-oocyte Foxo3a, a component of the phosphatidylinositol 3-kinase (PI3K) signaling pathway, influences follicular development and female fertility, a transgenic mouse model was generated with constitutively active Foxo3a expressed in oocytes. We found that the female transgenic mice were infertile, which was caused by retarded oocyte growth and follicular development, and anovulation. Further mechanistic studies revealed that the constitutively active Foxo3a in oocytes caused a dramatic reduction in the expression of bone morphogenic protein 15 (Bmp15), connexin 37 and connexin 43, which are important molecules for the establishment of paracrine and gap junction communications in follicles. Foxo3a was also found to facilitate the nuclear localization of p27(kip1) in oocytes, a cyclin-dependent kinase (Cdk) inhibitor that may serve to inhibit oocyte growth. The results from the current study indicate that Foxo3a is an important intra-oocyte signaling molecule that negatively regulates oocyte growth and follicular development. Our study may therefore give some insight into oocyte-borne genetic aberrations that cause defects in follicular development and anovulation in human diseases, such as premature ovarian failure.
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PMID:Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a. 1716 25

Cells expressing herpes simplex virus (HSV) thymidine kinase (tk) are killed by ganciclovir (GCV). Adjacent cells without HSV-tk also die, a phenomenon known as the 'bystander effect'. However, there is no evidence that replication-competent HSV induces a bystander effect in the presence of GCV. Therefore, we investigated the bystander effect in HEp-2 cells infected with replication-competent, oncolytic HSV-1 mutants, hrR3 and HF10. In cells infected at a multiplicity of infection (MOI) of 3, GCV did not induce apoptosis. At low MOIs of 0.3 and 0.03, however, a number of adjacent, uninfected cells apoptosed following GCV treatment. Irrespective of GCV treatment, HEp-2 cells expressed minimal levels of connexin 43 (Cx43). However, Cx43 expression was enhanced by GCV in response to infection with HF10 at an MOI of 0.3, but not at an MOI of 3. Expression of other proteins involved in gap junctions, including Cx26 and Cx40, was not augmented under these conditions. The PKA and PI3K signal transduction pathways are likely involved in enhanced Cx43 expression as inhibitors of these pathways prevented Cx43 upregulation. These results suggest that infection with replication-competent HSV-1 induces the bystander effect in cells treated with GCV because of efficient intercellular transport of active GCV through abundant gap junctions.
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PMID:Replication-competent, oncolytic herpes simplex virus type 1 mutants induce a bystander effect following ganciclovir treatment. 1768 93

Opening of unapposed connexin 43 hemichannels (Cx43Hc) in the plasma membrane results in altered ionic homeostasis leading to cell damage. Although it is generally acknowledged that Cx43Hc function is regulated by protein kinase C (PKC), information regarding the functional role of PKC in the modulation of Cx43Hc electrical conductance is lacking. In this work, we used the patch-clamp technique to study the effect of phorbol 12-myristate 13-acetate (PMA), a general PKC activator, on the electrical conductance of exogenous Cx43Hc expressed in tsA201 cells. Subsequently, a matrix of synthetic PKC isoform-specific inhibitor peptides was used to dissect the functional role of individual PKC isoforms in Cx43Hc regulation. Superfusion with 10 nM PMA abolished Cx43Hc currents by 74%, an effect that was prevented by pretreatment with a general PKC inhibitor, GF109203X. It is interesting to note that intracellular diffusion of epsilon V1-2 (0.1 microM), an epsilon PKC-specific inhibitor peptide, completely antagonized PMA-induced current inhibition. Cell dialysis with either beta II- or delta PKC inhibitor peptides partially decreased PMA effect. Neither alpha- nor beta I PKC inhibition altered PMA-induced current reduction. This study shows for the first time that Cx43Hc electrical conductance is inhibited after PKC activation. Moreover, this inhibition is predominantly mediated by the "novel" epsilon PKC isoform, whereas partial inhibition may be provided by the "conventional" beta II PKC as well as the "novel" delta PKC isoforms.
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PMID:Differential modulation of unapposed connexin 43 hemichannel electrical conductance by protein kinase C isoforms. 1817 2

The Bowman-Birk inhibitor (BBI) is a small water-soluble protein present in soybean and almost all monocotyledonous and dicotyledonous seeds. The molecular size of BBI ranges from 1,513 Da to about 20,000 Da. BBI is to seeds what alpha(1)-antitrypsin is to humans. Soy-based food products rich in BBI include soybean grits, soymilk, oilcake, soybean isolate, and soybean protein concentrate. BBI is stable within the pH range encountered in most foods, can withstand boiling water temperature for 10 min, resistant to the pH range and proteolytic enzymes of the gastrointestinal tract, bioavailable, and not allergenic. BBI reduces the proteolytic activities of trypsin, chymotrypsin, elastase, cathepsin G, and chymase, serine protease-dependent matrix metalloproteinases, urokinase protein activator, mitogen activated protein kinase, and PI3 kinase, and upregulates connexin 43 (Cx43) expression. Several studies have demonstrated the efficacy of BBI against tumor cells in vitro, animal models, and human phase IIa clinical trials. FDA considers BBI as a drug. In 1999, FDA allowed a health claim on food labels stating that a daily diet containing 25 grams of soy protein, also low in saturated fat and cholesterol, may reduce the risk of heart disease [corrected] This review highlights the biochemical and functional food properties of the Bowman-Birk inhibitor.
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PMID:The biochemical and functional food properties of the bowman-birk inhibitor. 1827 67

(-)-Epigallocatechin gallate (EGCG), a polyphenolic compound found in green tea, is a promising chemopreventive agent against cancer due to its strong antiproliferative effects on cancer cells; however, its possible toxicity and carcinogenicity must be investigated before EGCG can be used as a dietary supplement for chemoprevention. The inhibition of gap junctional intercellular communication (GJIC) is strongly associated with carcinogenesis, particularly the tumor promotion process; thus, we investigated the effects of EGCG on GJIC in WB-F344 normal rat liver epithelial (RLE) cells. EGCG, but not (-)-epicatechin (EC), another polyphenol found in green tea, inhibited GJIC in a dose-dependent and reversible manner in RLE cells. EGCG also induced the phosphorylation of connexin 43 (Cx43), a major regulator of GJIC. The phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) was also observed in EGCG-treated RLE cells. The inhibition of GJIC and phosphorylation of Cx43 and ERK1/2 by EGCG were completely blocked by U0126, a pharmacological inhibitor of mitogen-activated protein kinase/ERK kinase. EGCG generated a larger amount of hydrogen peroxide than EC in a dose-dependent manner. Furthermore, catalase partially inhibited the EGCG-induced inhibition of GJIC and the phosphorylation of Cx43 and ERK1/2. These results indicated that EGCG inhibited GJIC mainly due to its prooxidant activity.
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PMID:Inhibition of gap junctional intercellular communication by the green tea polyphenol (-)-epigallocatechin gallate in normal rat liver epithelial cells. 1882 1

An incomplete understanding of the molecular events that regulate the myometrial transition from the quiescent pregnant state to the active contractile state during labor has hindered the development of improved therapies for preterm labor. During myometrial activation, proteins that prime the smooth muscle for contraction are upregulated, allowing maximal responsiveness to contractile agonists and thereby producing strong phasic contractions. Upregulation of one such protein, COX-2, generates PGs that induce contractions. Intriguingly, the predominant myometrial PG produced just prior to labor is prostacyclin (PGI2), a smooth muscle relaxant. However, here we have shown that activation of PGI2 receptor (IP) upregulated the expression of several contractile proteins and the gap junction protein connexin 43 through cAMP/PKA signaling in human myometrial tissue in organ and cell culture. Functionally, these IP-dependent changes in gene expression promoted an enhanced contractile response to oxytocin in pregnant human myometrial tissue strips, which was inhibited by the IP antagonist RO3244794. Furthermore, contractile protein induction was dependent on the concentration and time of exposure to the PGI2 analog iloprost and was blocked by both RO3244794 and PKA knockdown. We therefore propose that PGI2-mediated upregulation of contractile proteins and connexin 43 is a critical step in myometrial activation, allowing for a maximal contractile response. Our observations have important implications regarding activation of the myometrium prior to the onset of labor.
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PMID:Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition. 1903 50

A dysfunction of the cardiac gap junction, which contributes to electrical cell-to-cell coupling is one of essential factors known to generate arrhythmias. The function of the gap junction depends on the regulation of connexin which composes the gap junction channel. A dysfunction of the gap junction is possibly caused by the down-regulation of connexin. In this review, the relationship between pathological remodeling of connexin 43 (Cx43) and susceptibility of the heart to the ventricular fibrillation, which is a lethal ventricular tachyarrhythmia, is addressed. A suppression of the PKA-mediated phosphorylation or an augmentation of the PKC-mediated phosphorylation of Cx43 induces the downward remodeling of Cx43. Factors regarding downward remodeling of Cx43, such as hypoxia (including intracellular Ca overload and intracellular acidosis), angiotensin II or an activation of PKCvarepsilon make the heart more susceptible to the ventricular fibrillation, while factors regarding upward remodeling of Cx43, such as cyclic AMP or an activation of PKA, lower susceptibility. As a result, from a clinical point of view, angiotensin II antagonists (synthesis inhibitors or receptor blockades), PKC inhibitors or PKA activators are thus considered to provide a therapeutic approach for the treatment of the initiation or advancement of the ventricular fibrillation.
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PMID:Pathological remodeling of cardiac gap junction connexin 43-With special reference to arrhythmogenesis. 1954 Jul 36

In cardiac muscle, the gap junction contributes to electrical cell-to-cell coupling. This physiological function of the gap junction depends on the phosphorylation state of the connexin molecule, which comprises the gap junction channel. The effects of intracellular Ca(2+) overload, acidosis, activation of protein kinase (PK) A, PKC and PKG on the phosphorylation and expression of connexin 43 (Cx43) were examined in animal hearts with reference to physiological function. Activation of PKA promotes cell-to-cell coupling due to augmentation of the PKA-mediated phosphorylation of Cx43, with a rise in the quantity of and an increase in the expression of Cx43. A rise in the ionic strength of Ca(2+) and H(+) impaired cell communication, with the inhibition of PKA-mediated Cx43 phosphorylation. Activation of PKC reduces the quantity and expression of Cx43 despite augmentation of PKC-mediated phosphorylation of the protein. The effects of PKG activation are similar to those of PKC activation. It is suggested that PKA activation upregulates and PKC activation downregulates Cx43. The role of connexin phosphorylation in the regulation of gap junction function is discussed.
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PMID:Phosphorylation of connexin in functional regulation of the cardiac gap junction. 1964 18


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