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 imidazoquinolineamine derivative 1-(2-methyl propyl)-1H-imidazole [4,5-c]quinoline-4-amine (imiquimod) has been shown to induce alpha interferon (IFN-alpha) synthesis both in vivo and in peripheral blood mononuclear cells in vitro. In this study, we show that, in these cells, imiquimod induces expression of several IFNA genes (IFNA1, IFNA2, IFNA5, IFNA6, and IFNA8) as well as the IFNB gene. Imiquimod also induced the expression of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha genes. Expression of all these genes was transient, independent of cellular protein synthesis, and inhibited in the presence of tyrosine kinase and protein kinase C inhibitors. Infection with Sendai virus led to expression of a similar set of cytokine genes and several of the IFNA genes. Imiquimod stimulates binding of several induction-specific nuclear complexes: (i) the NF-kappa B-specific complexes binding to the kappa B enhancer present in the promoters of all cytokine genes, but not in IFNA genes, and (ii) the complex(es) binding to the A4F1 site, 5'-GTAAAGAAAGT-3', conserved in the inducible element of IFNA genes. These results indicate that imiquimod, similar to viral infection, stimulates expression of a large number of cytokine genes, including IFN-alpha/beta, and that the signal transduction pathway induced by both of these stimuli requires tyrosine kinase and protein kinase activity.
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PMID:Stimulation of interferon and cytokine gene expression by imiquimod and stimulation by Sendai virus utilize similar signal transduction pathways. 753 79

The properties of the cystic fibrosis gene product (CFTR) were studied by expression of cloned cDNA in different cell systems. Infection of both simian fibroblast (Vero) cells and immortalized CF nasal polyp cells (NCF3A) with a vaccinia virus encoding CFTR induced forskolin-induced Cl- permeability and low-conductance (8 pS) Cl- channels. By stable transfection of the rat intestinal crypt-derived cell line IEC-6 we have isolated a clone, IEC-CF7, which expresses CFTR mRNA and antigen. IEC-CF7 cells, but not IEC-6, display forskolin-induced Cl- permeability and multiple linear low-conductance (+/- 8 pS) Cl- channels in cell-attached membrane patches. In excised patches of IEC-CF7 cells, low-conductance Cl- channels could be activated by addition of the catalytic subunit of the adenosine 3',5'-cyclic monophosphate-dependent protein kinase A (PKA) plus ATP. During bath fluid replacement studies, the activated low-conductance channel remained active in the absence of ATP at room temperature and showed saturation kinetics. Rectifying (32 pS) Cl- channels were not observed in either IEC-6 cells or IEC-CF7 cells, indicating that there is no relation between CFTR expression and the incidence of this channel. Our data strongly support the conclusion that CFTR can act as a low-conductance Cl- channel, gated by PKA. The IEC-6-derived cell line IEC-CF7 may prove to be a useful model in the study of CFTR function because of the absence of 32-pS Cl- channel activity and its potential for differentiation.
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PMID:Low-conductance chloride channels in IEC-6 and CF nasal cells expressing CFTR. 768 32

Infection of cattle with the protozoan parasite Theileria parva results in a fatal lymphoproliferative syndrome that is associated with the overexpression of casein kinase II. The role of this enzyme in the pathogenesis of lymphoproliferative disorders was investigated by expressing the catalytic subunit in lymphocytes of transgenic mice. Adult transgenic mice displayed a stochastic propensity to develop lymphoma; co-expression of a c-myc transgene in addition to casein kinase II resulted in neonatal leukemia. Thus, the casein kinase II gene can serve as an oncogene, and its dysregulated expression is capable of transforming lymphocytes in a two-step pathway with c-myc.
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PMID:Casein kinase II alpha transgene-induced murine lymphoma: relation to theileriosis in cattle. 784 27

Signal-transduction pathways mediate a wide range of short-term changes in the physiology of neuronal systems from invertebrates to mammals. However, examples of long-term changes in neuronal physiology mediated by these pathways have been limited to invertebrate systems. In this report, long-term changes in the physiology of mammalian neurons were studied by using genetic intervention to cause a long-lasting activation of the cAMP pathway. The catalytic domain of yeast adenylate cyclase (cyr), encoding a constitutive enzyme activity, was expressed in neuronal cells infected with a defective herpes simplex virus vector (pHSVcyr). In PC-12 cells infected with pHSVcyr, increases were seen in cAMP levels, protein kinase A activity, protein phosphorylation, phosphorylation of the tyrosine hydroxylase protein kinase A site (Ser40), and catecholamine release. Infection of sympathetic neurons with pHSVcyr increased cAMP levels, protein phosphorylation, and catecholamine release. Yeast adenylate cyclase immunoreactivity and elevated cAMP levels were localized to the cell bodies of sympathetic neurons. The increase in neurotransmitter release was both Ca(2+)- and activity-dependent and persisted for at least 1 week after infection of the sympathetic neurons, suggesting that sustained physiological activation of the cAMP pathway may mediate long-term changes in the neuronal physiology of mammalian systems.
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PMID:Long-term increases in neurotransmitter release from neuronal cells expressing a constitutively active adenylate cyclase from a herpes simplex virus type 1 vector. 810 99

Infection of cells with adenovirus or transfection of cells with double-stranded RNA (dsRNA) activates transcription of the alpha/beta interferon-stimulated genes (ISGs). Induction of ISG expression by adenovirus appears to be mediated through the same DNA target that is responsive to alpha/beta interferons, the interferon-stimulated response element (ISRE). Transcriptional induction by alpha/beta interferons has been shown previously to be mediated by the activation of a latent cytoplasmic transcription factor, ISGF3, that translocates to the nucleus and binds to the ISRE. However, ISG expression induced by adenovirus or dsRNA appears to be mediated by unique dsRNA-activated factors (DRAFs) that bind to the ISRE. The activation of these preexisting factors by dsRNA does not require new protein synthesis. Two DRAFs, DRAF1 and DRAF2, have been identified in our studies as ISRE-binding complexes in gel mobility shift assays. The ISRE-binding specificity of DRAF1 is similar to that of ISGF3; however, the ISRE-binding specificity of DRAF2 is distinct. Activation of DRAF1 and DRAF2 is independent of interferon action since it occurs in cells that are nonresponsive to interferon and in cells that lack the alpha/beta interferon locus. The activation pathway of DRAF1 and DRAF2 is blocked by the protein kinase inhibitors staurosporine and genistein. This is analogous to the interferon signal transduction pathway and suggests that phosphorylation, possibly tyrosine phosphorylation, is involved in activation of these factors.
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PMID:Double-stranded RNA activates novel factors that bind to the interferon-stimulated response element. 838 46

Adult rat chromaffin cells in vitro show a large proliferative response to NGF, followed by neuronal differentiation. Infection of replicating chromaffin cells with a retrovirus carrying the Escherichia coli beta-galactosidase (beta-gal) gene demonstrates beta-gal expression in cells that continue to multiply, that differentiate into neurons, and that become static. The effects of NGF on proliferation and differentiation are abolished by the protein kinase inhibitors K252a and staurosporine, and by cholera toxin, an activator of adenylate cyclase. They are diminished, but not abolished, by high concentrations of dexamethasone. Both cholera toxin alone and phorbol myristate acetate (PMA), an activator of protein kinase C, elicit small and inconsistent mitogenic responses. The responses to PMA cannot be shown to be additive with the effects of NGF. NGF is a known mitogen and neuritogen for chromaffin cells from neonatal rats, but has not previously been believed to affect similarly chromaffin cells from adults. The present findings suggest that portions of NGF signaling pathways might continue to be involved in regulating proliferation of adult rat chromaffin cells in vivo, and might be constitutively activated in PC12 cells and other adrenal medullary tumors. They further suggest that rat chromaffin cells might be propagated in vitro to obtain large numbers of sympathetic neurons expressing normal or exogenous genes.
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PMID:Nerve growth factor is a potent inducer of proliferation and neuronal differentiation for adult rat chromaffin cells in vitro. 846 33

Infection of human primary B-lymphocytes with Epstein-Barr virus (EBV) drives quiescent cells into continual proliferation and results in the outgrowth of immortal cell lines. This requires re-programming of the mechanisms that, in the absence of appropriate antigenic stimulation, normally prevent the proliferation of B-lymphocytes. Since the Retinoblastoma protein (pRb) and its relatives, p107 and p130, play critical roles in controlling the mammalian cell division cycle, we have investigated the expression and phosphorylation status of these proteins following EBV immortalisation of primary B-lymphocytes. In this report, we show that EBV drives the hyperphosphorylation of pRb. This is achieved by a strategy involving the altered expression of several components of the signal transduction pathway that normally regulates the phosphorylation status of pRb, including the up regulation of a number of cyclins and cyclin-dependent kinases and the down regulation of a subset of cyclin-dependent kinase inhibitors. The net result is the formation of active cyclin-dependent kinase complexes that are capable of phosphorylating and inactivating pRb. The results presented here identify the activation of a normal signal transduction pathway as an important component of the strategy used by EBV to drive cell proliferation.
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PMID:Epstein-Barr virus exploits the normal cell pathway to regulate Rb activity during the immortalisation of primary B-cells. 887 79

The vaccinia virus E3L gene codes for double-stranded RNA (dsRNA) binding proteins which can prevent activation of the dsRNA-dependent, interferon-induced protein kinase PKR. Activated PKR has been shown to induce apoptosis in HeLa cells. HeLa cells infected with vaccinia virus with the E3L gene deleted have also been shown to undergo apoptosis, whereas HeLa cells infected with wild-type vaccinia virus do not. In this report, using virus recombinants expressing mutant E3L products or alternative dsRNA binding proteins, we show that suppression of induction of apoptosis correlates with functional binding of proteins to dsRNA. Infection of HeLa cells with ts23, which leads to synthesis of increased dsRNA at restrictive temperature, induced apoptosis at restrictive but not permissive temperatures. Treatment of cells with cytosine arabinoside, which blocks the late buildup of dsRNA in vaccinia virus-infected cells, prevented induction of apoptosis by vaccinia virus with E3L deleted. Cells transfected with dsRNA in the absence of virus infection also underwent apoptosis. These results suggest that dsRNA is a trigger that can initiate a suicide response in virus-infected and perhaps uninfected cells.
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PMID:Double-stranded RNA is a trigger for apoptosis in vaccinia virus-infected cells. 903 31

Cells expressing human papillomavirus type 16 (HPV-16) E7, similar to those which express HPV-16 E6, are resistant to a p53-mediated G1 growth arrest. We examined the p53-mediated DNA damage response pathway in E7-expressing cells to determine the mechanism by which E7-containing cells continue to cycle. In response to DNA damage, no dramatic difference was detected in G1- or S-phase cyclin or cyclin-dependent kinase (Cdk) levels when E7-expressing cells were compared to the parental cell line, RKO. Furthermore, Cdk2 kinase activity was inhibited in both RKO cells and E7-expressing cells, while Cdk2 remained active in E6-expressing cells. However, the steady-state levels of pRB and p107 protein were substantially lower in E7-expressing cells than in the parental RKO cells or E6-expressing cells. There was no reduction in pRB mRNA levels, but the half-life of pRB in E7-expressing cells was markedly shorter. Infection of primary human foreskin keratinocytes with recombinant retroviruses expressing HPV-16 E7 resulted in a decrease in pRB protein levels, indicating this phenomenon is a consequence of E7 expression, not of immortalization or transformation. These data strongly suggest E7 interferes with the stability of pRB and p107 protein. We propose that the removal of these components of the p53-mediated G1 growth arrest pathway in E7-expressing cells contributes to the ability of E7 to overcome a p53-mediated G1 growth arrest.
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PMID:Analysis of the p53-mediated G1 growth arrest pathway in cells expressing the human papillomavirus type 16 E7 oncoprotein. 906 Jun 48

The E7 oncoproteins encoded by the high-risk type of human papillomaviruses (HPVs) interact with the Rb family proteins Rb, p107, and p130. The Rb family proteins associate with the factors of the E2F family to form transcription repressor complexes, which control expression of several genes essential for S-phase entry and DNA replication. The E7 oncoproteins, by interacting with the Rb family proteins, dissociate the repressor complexes involving the factors of the E2F and Rb families, leading to a release of the E2F factors in their activator forms. In this study, we have addressed the mechanism by which the HPV type 16 (HPV16) E7 stimulates the cell cycle. Using a cell line that inducibly expresses the HPV16 E7 protein, we show that an accumulation of E7 induces quiescent cells to enter S phase and that this function of E7 depends on retention of the motif involved in binding to the Rb family proteins. To study the effects of E7 on normal human cells, we generated a recombinant adenovirus that expresses the HPV16 E7 protein. Infection of normal human fibroblasts, which were arrested in G1 phase by serum deprivation, with the E7-expressing virus induced the cells to enter S phase. The E7-induced S phase entry was accompanied by an increase in the activator form of E2F, but no increase in the cyclin-dependent kinase (cdk) activity was detected. Infection of serum-stimulated fibroblasts with a recombinant adenovirus expressing the cdk inhibitor p21 inhibited progression into S phase. Coinfection with the E7-expressing virus abrogated the p21 inhibition of progression into S phase without increasing the cdk activity. These results are consistent with the notion that E7 stimulates entry into S phase through targets downstream of the cdks such as the proteins of the E2F and Rb families.
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PMID:Accumulation of human papillomavirus type 16 E7 protein bypasses G1 arrest induced by serum deprivation and by the cell cycle inhibitor p21. 909 16


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