Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protein kinase C-(PKC) activating phorbol esters 12-O-tetradecanoylphorbol-13-acetate (TPA; 100 nmol/l) and phorbol 12,13-dibutyrate (PDBU; 100 nmol/l) enhanced basal cyclin AMP accumulation in cultured neonatal mouse calvaria. The cyclic AMP response to parathyroid hormone (PTH; 10 nmol/l) and the adenylate cyclase activators forskolin (1-3 mumol/l) and choleratoxin (0.1 mumg/ml) was potentiated in a more than additive manner by TPA and PDBU. In contrast, phorbol 13-monoacetate (phorb-13; 100 nmol/l), a related compound but inactive on PKC, had no effect on basal or stimulated cyclic AMP accumulation. In the presence of indomethacin (1 mumol/l), TPA and PDBU had no effect on cyclic AMP accumulation in calvarial bones per se, but were still able to cause a significant enhancement of the response to PTH, forskolin and choleratoxin. PTH-, forskolin- and choleratoxin-stimulated cyclic AMP accumulation in rat osteosarcoma cells UMR 106-01 was synergistically potentiated by TPA and PDBU, but not by phorb.-13. These data indicate that PKC enhances cyclic AMP formation and that the level of interaction may be at, or distal to, adenylate cyclase.
 ...
PMID:Protein kinase C activating phorbolesters enhance the cyclic AMP response to parathyroid hormone, forskolin and choleratoxin in mouse calvarial bones and rat osteosarcoma cells. 166 87

Prothymosin alpha (ProT alpha) is a widely distributed acidic protein whose function has been related to cell proliferation. We have analyzed the expression of the rat ProT alpha gene in several proliferative systems: concanavalin A (ConA)/interleukin-2-stimulated thymocytes, ConA-stimulated splenic T-lymphocytes, and hepatocytes proliferating during liver regeneration. In these systems, ProT alpha mRNA was detected in all stages of the cell cycle, with maximal increments (2-4-fold) at the beginning of the S phase. By contrast, the mRNAs for proliferating cell nuclear antigen/cyclin and histone H3, two cell-cycle-regulated proteins, were hardly detected in resting cells but increased notably at the G1/S boundary and in the S phase, respectively. Treatment of T-cells with the calcium ionophore A23187 increased ProT alpha mRNA levels 2.5-fold, whereas phorbol 12-myristate 13-acetate, a protein kinase C activator, had no effect on ProT alpha gene expression. Incubation of ConA-stimulated T-cells with hydroxyurea, a DNA synthesis inhibitor, did not decrease the levels of ProT alpha mRNA, indicating that its expression is independent of DNA synthesis. These findings suggest that ProT alpha is required throughout all the stages of the cell cycle, resembling a constitutively expressed gene rather than one strictly involved in cell proliferation.
 ...
PMID:Expression of the rat prothymosin alpha gene during T-lymphocyte proliferation and liver regeneration. 167 Oct 35

We have used light-microscopical immunohistochemistry to investigate developmental changes of several neurochemical indicators in retinas of perinatal killifish and goldfish. Immunoreactive proliferating cell nuclear antigen (ir-PCNA/cyclin, a marker for replicating cells) was present in nuclei of all neuroblasts in the early monolayer stage, but was lost progressively in central-to-peripheral and proximal-to-distal order as the layers and cells of the mature retina appeared. The loss of ir-PCNA was slightly prior to the appearance of ir-TH (tyrosine hydroxylase), GAD (glutamic acid decarboxylase) and GS (glutamine synthetase) at the 4th embryonic day (E4) in both fish. Since hatching was earlier in goldfish (E5) than in killifish (E7), neurochemical maturation was evident at 2-3 days before hatching in killifish but not until around hatching in goldfish. Two markers, ir-somatostatin and protein kinase C, were detected by the 1st postnatal day (H1) in goldfish, but not in perinatal or adult killifish retinas. Thus the course of development of killifish and goldfish retinas is similar, but not identical. The validity of ir-PCNA as a marker for proliferating cells is confirmed by the coincidence of its disappearance with the appearance of neurochemical markers for mature, postmitotic retinal cells.
 ...
PMID:Emergence and development of immunoreactive cells in teleostean retinas during the perinatal period. 197 54

WAF1 inhibits cyclin-cyclin dependent kinase complexes, causing arrest in the cell cycle. We report that interleukin-1 (IL-1) regulates the levels of WAF1 protein and mRNA in human fibroblasts. Further studies showed that 12-O-tetradecanoyl phorbol 13-acetate (TPA) enhanced the accumulation of WAF1; cells refractory to TPA still increased their levels of WAF1 mRNA when exposed to IL-1. IL-1 also increased transcription of WAF1 by 13-fold and WAF1 mRNA became 2-fold more stable in cells stimulated with IL-1 (t1/2 = 2 h) as compared to untreated cells (t1/2 = 1 h). In summary, IL-1 induces expression of WAF1, and this occurs by increased transcription of WAF1 and stabilization of WAF1 mRNA. Our data also indicate that the induction of WAF1 mRNA by IL-1 occurs through a pathway independent of protein kinase C activation.
 ...
PMID:IL-1 induces expression of WAF1 mRNA in human fibroblasts: mechanisms of accumulation. 748 30

Since PKC epsilon functions as an oncogene when stably overexpressed in R6 rat fibroblasts (Cacace et al. 1993) in the present study we examined whether transformed R6-PKC epsilon cells display abnormalities in the expression of specific early response and cyclin genes. When vector control and R6-PKC epsilon cells were starved of serum for 72 h they arrested in G0/G1 and showed passage through the cell cycle at similar rates after subsequent stimulation with 10% fetal calf serum plus TPA. In PKC epsilon cells, induction of cyclin D1 protein was markedly reduced, and that of cyclin A was slightly reduced when compared to control cells. Northern blot analyses indicated that decreased expression of cyclin D1 and A protein in PKC epsilon cells is due to translational or post-translational effects. A study of early response gene expression in PKC epsilon cells indicated that there was a marked reduction in the expression of c-fos mRNA but not in c-jun or c-myc mRNAs. The marked decreases in cyclin D1 and c-fos expression seen in PKC epsilon cells were not seen in R6 cells that overexpress PKCs alpha or beta. These findings suggest that PKC epsilon cells bypass certain normal signal transduction and cyclin-controlled pathways involved in cell proliferation.
 ...
PMID:Altered expression of cyclins and c-fos in R6 cells that overproduce PKC epsilon. 758 46

Cell cycle is regulated by the activation of complexes of cyclins and cyclin-dependent protein kinases at specific points. Quiescent cells lack both cyclins and cyclin-dependent kinases but their expression is induced after proliferative activation. Cyclin A/cdk2 complexes are involved in the onset of DNA replication whereas cyclin B/cdc2 trigger mitosis. We report here that Ca2+ and calmodulin regulate the expression of cdk2, cdc2, cyclin B and the proliferating cell nuclear antigen (a co-factor of DNA polymerase-delta) in human T lymphocytes. Likewise, the expression of cdk4, cyclin A and DNA polymerase-alpha is dependent of the synergistic effect of both the Ca2+/calmodulin and the protein kinase C pathways. Thus, calmodulin controls DNA synthesis by regulating the levels of cdk2 and proliferating cell nuclear antigen and mitosis entry by modulating the expression of cyclin B and cdc2.
 ...
PMID:Calmodulin regulates the expression of cdks, cyclins and replicative enzymes during proliferative activation of human T lymphocytes. 790 33

While testing purines related to the non-specific protein kinase inhibitors N6-dimethylaminopurine and N6-(delta 2-isopentenyl)adenine as potential inhibitors of the p34cdc2/cyclin B kinase, we discovered a compound with high specificity, 2-(2-hydroxyethylamino)-6- benzylamino-9-methylpurine (olomoucine). Kinetic analysis of kinase inhibition reveals that olomoucine behaves as a competitive inhibitor for ATP and as a non-competitive inhibitor for histone H1 (linear inhibition for both substrates). The kinase specificity of this inhibition was investigated for 35 highly purified kinases (including p34cdk4/cyclin D1, p40cdk6/cyclin D3, cAMP-dependent and cGMP-dependent kinases, eight protein kinase C isoforms, calmodulin-dependent kinase II, myosin light-chain kinase, mitogen-activated S6 kinase, casein kinase 2, double-stranded RNA-activated protein kinase, AMP-stimulated kinase, eight tyrosine kinases). Most kinases are not significantly inhibited. Only the cell-cycle regulating p34cdc2/cyclin B, p33cdk2/cyclin A and p33cdk2/cyclin E kinases, the brain p33cdk5/p35 kinase and the ERK1/MAP-kinase (and its starfish homologue p44mpk) are substantially inhibited by olomoucine (IC50 values are 7, 7, 7, 3 and 25 microM, respectively). The cdk4/cyclin D1 and cdk6/cyclin D3 kinases are not significantly sensitive to olomoucine (IC50 values greater than 1 mM and 150 microM, respectively). N6-(delta 2-Isopentenyl)adenine is confirmed as a general kinase inhibitor with IC50 values of 50-100 microM for many kinases. The purine specificity of cyclin-dependent kinase inhibition was investigated: among 81 purine derivatives tested, only C2, N6 and N9-substituted purines exert a strong inhibitory effect on the p34cdc2/cyclin B kinase. An essentially similar sensitivity to this olomoucine family of compounds was observed for the brain-specific cdk5/p35 kinase. Structure/activity relationship studies allow speculation on the interactions of olomoucine and its analogues with the kinase catalytic subunit. Olomoucine inhibits in vitro M-phase-promoting factor activity in metaphase-arrested Xenopus egg extracts, inhibits in vitro DNA synthesis in Xenopus interphase egg extracts and inhibits the licensing factor, an essential replication factor ensuring that DNA is replicated only once in each cell cycle. Olomoucine inhibits the starfish oocyte G2/M transition in vivo. Through its unique selectivity olomoucine provides an anti-mitotic reagent that may preferentially inhibit certain steps of the cell cycle.
 ...
PMID:Inhibition of cyclin-dependent kinases by purine analogues. 792 96

Previously pp60v-src, cyclin A, p39mos, and maturation-promoting factor (composed of Cdc2 and cyclin B) have been shown to activate mitogen-activated protein kinase (MAPK) and MAPK kinase (MEK) in cell-free extracts of Xenopus oocytes. The pp60v-src pathway is dependent on a functional Ras signal whereas the cyclin/maturation-promoting factor pathway is not. Here we show that protein kinase C (PKC) is also able to stimulate MAPK in a Ras-dependent manner, but PKC is not necessary for signaling by pp60v-src. In addition, preincubation of extracts with cAMP-dependent protein kinase (PKA) blocks stimulation of MAPK by cyclin, p21V12ras, PKC, or pp60v-src, by at least 50%, but stimulation by c-Mos is unaffected. Furthermore, inhibition of endogenous PKA by the heat-stable PKA inhibitor is sufficient to stimulate MAPK activity in these extracts in the absence of protein synthesis and without dependence on a functional Ras protein. These results suggest that independent pp60v-src and PKC pathways converge at Ras and that PKA acts to block MAPK activation by both Ras-dependent and -independent signals.
 ...
PMID:Regulation of mitogen-activated protein kinase activation by protein kinases A and C in a cell-free system. 792 38

Multisite phosphorylation of the nuclear lamins is thought to regulate the process of mitotic nuclear envelope breakdown in vivo. Here we investigate the involvement of two proposed human mitotic lamin kinases, beta II protein kinase C (PKC) and p34cdc2/cyclin B kinase, in human lamin B1 phosphorylation in vitro and in intact cells. We find that both kinases can phosphorylate purified soluble lamin B at similar rates. However, beta II PKC phosphorylates interphase nuclear envelope lamin B at more than 200 times the rate of human p34cdc2/cyclin B kinase. beta II PKC-mediated phosphorylation of lamin B is confined to two sites, Ser395 and Ser405, within the carboxyl-terminal domain, whereas human p34cdc2/cyclin B kinase phosphorylates a single site, Ser23, in the amino-terminal domain. A second potential p34cdc2/cyclin B kinase site within the carboxyl-terminal domain, Ser393, is not phosphorylated by human p34cdc2/cyclin B kinase. However, invertebrate p34cdc2/cyclin B kinase from sea star exhibits a different specificity, phosphorylating both amino- and carboxyl-terminal sites. Mitotic human lamin B from intact cells is phosphorylated predominantly in its carboxyl-terminal domain. Comparative tryptic phosphopeptide mapping demonstrates that the beta II PKC site, Ser405, is a prominent target of mitotic lamin B phosphorylation in vivo. beta II PKC translocates to the nucleus during the G2/M phase of cell cycle concomitant with phosphorylation of Ser405, indicating a physiologic role for nuclear beta II PKC activation in mitotic lamin B phosphorylation in vivo. The presence of phosphorylation sites within the carboxyl-terminal domain of mitotic lamin B which are not phosphorylated by either beta II PKC or p34cdc2/cyclin B kinase suggests the involvement of other lamin kinase(s) in G2/M phase lamin B phosphorylation.
 ...
PMID:Identification of nuclear beta II protein kinase C as a mitotic lamin kinase. 803 66

Activation of muscle gene transcription in differentiating skeletal myoblasts requires their withdrawal from the cell cycle. The effects of ectopic cyclin expression on activation of muscle gene transcription by myogenic basic helix-loop-helix (bHLH) regulators were investigated. Ectopic expression of cyclin D1, but not cyclins A, B1, B2, C, D3, and E, inhibited transcriptional activation of muscle gene reporter constructs by myogenic bHLH regulators in a dose-dependent manner. Ectopic expression of cyclin D1 inhibited the activity of a myogenic bHLH regulator mutant lacking the basic region protein kinase C site, indicating that phosphorylation of this site is not relevant to the mechanism of inhibition. Analysis of cyclin D1 mutants revealed that the C-terminal acidic region was required for inhibition of myogenic bHLH regulator activity, whereas an intact N-terminal pRb binding motif was not essential. Together, these results implicate expression of cyclin D1 as a central determinant of a putatively novel mechanism that links positive control of cell cycle progression to negative regulation of genes expressed in differentiated myocytes.
 ...
PMID:Ectopic expression of cyclin D1 prevents activation of gene transcription by myogenic basic helix-loop-helix regulators. 803 4


1 2 3 4 5 6 7 8 9 10 Next >>