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)

Signal transduction pathway and a new function of TIS21/BTG2/PC3 were investigated in p53 null U937 cells; Expression of TIS21 by 12-O-tetradecanoyl phorbol-13-acetate (TPA) stimulation was mediated by PKC-delta activation, however, was strongly inhibited by cPKC isozymes. When U937 cells were treated with TPA+Go6976, but not TPA+Go6850, the level of TIS21 mRNA was maintained over that of TPA alone. When analyzed by FACS, TPA-induced G2/M arrest was significantly inhibited by Go6850, but not by Go6976, suggesting the involvement of TIS21 and nPKC isozymes. Indeed, PKC-delta was found to be a regulator of the G2/M arrest and TIS21 expression, confirmed by employing rottlerin and dnPKC-delta experiments. In vivo accumulation of TIS21 protein significantly induced cell death through caspase 3 activation, which was supported further by degradations of procaspase 3, full-length PKC-delta, pRB, and p21(WAF1) in TIS21DeltaC expresser. When the cells were synchronized by nocodazole, TIS21 overexpressers inhibited degradations of cyclin A and cyclin B1 in 3 h after release from the synchronization. Furthermore, TIS21 inhibited cyclin B1-Cdc2 binding and its kinase activity in vivo. In summary, TPA-induced TIS21 mRNA expression is mediated by PKC-delta, and TIS21 induces G2/M arrest and cell death by inhibiting cyclin B1-Cdc2 binding and the kinase activity through its binding to Cdc2.
 ...
PMID:TIS21/BTG2/PC3 is expressed through PKC-delta pathway and inhibits binding of cyclin B1-Cdc2 and its activity, independent of p53 expression. 1530 83

Integrin-mediated adhesion of epithelial cells to extracellular matrix (ECM) proteins induces prolonged tyrosine phosphorylation and partial activation of epidermal growth factor receptor (EGFR) in an integrin-dependent and EGFR ligand-independent manner. Integrin-mediated activation of EGFR in epithelial cells is required for multiple signal transduction events previously shown to be induced by cell adhesion to matrix proteins, including tyrosine phosphorylation of Shc, Cbl, and phospholipase Cgamma, and activation of the Ras/Erk and phosphatidylinositol 3'-kinase/Akt signaling pathways. In contrast, activation of focal adhesion kinase, Src, and protein kinase C, adhesion to matrix proteins, cell spreading, migration, and actin cytoskeletal rearrangements are induced independently of EGFR kinase activity. The ability of integrins to induce the activation of EGFR and its subsequent regulation of Erk and Akt activation permitted adhesion-dependent induction of cyclin D1 and p21, Rb phosphorylation, and activation of cdk4 in epithelial cells in the absence of exogenous growth factors. Adhesion of epithelial cells to the ECM failed to efficiently induce degradation of p27, to induce cdk2 activity, or to induce Myc and cyclin A synthesis; subsequently, cells did not progress into S phase. Treatment of ECM-adherent cells with EGF, or overexpression of EGFR or Myc, resulted in restoration of late-G(1) cell cycle events and progression into S phase. These results indicate that partial activation of EGFR by integrin receptors plays an important role in mediating events triggered by epithelial cell attachment to ECM; EGFR is necessary for activation of multiple integrin-induced signaling enzymes and sufficient for early events in G(1) cell cycle progression. Furthermore, these findings suggest that EGFR or Myc overexpression may provoke ligand-independent proliferation in matrix-attached cells in vivo and could contribute to carcinoma development.
 ...
PMID:Epidermal growth factor receptor-dependent regulation of integrin-mediated signaling and cell cycle entry in epithelial cells. 1536 78

In the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant glioma cells, treatment with TRAIL in combination with subtoxic doses of rottlerin induced rapid apoptosis. While the proteolytic processing of procaspase-3 by TRAIL was partially blocked in these cells, treatment with rottlerin efficiently recovered TRAIL-induced activation of caspases. Treatment with rottlerin significantly decreased Cdc2 activity through the downregulation of cyclin A, cyclin B, and Cdc2 proteins, whereas the sensitizing effect of rottlerin on TRAIL-induced apoptosis was independent of PKCdelta activity. Furthermore, treatment with rottlerin downregulated the protein levels of survivin and X-chromosome-linked IAP (XIAP), two major caspase inhibitors. Forced expression of Cdc2 together with cyclin B attenuated rottlerin-potentiated TRAIL-induced apoptosis by over-riding the rottlerin-mediated downregulation of survivin and XIAP protein levels. Taken together, inhibition of Cdc2 activity and the subsequent downregulation of survivin and XIAP by subtoxic doses of rottlerin contribute to amplification of caspase cascades, thereby overcoming resistance of glioma cells to TRAIL-mediated apoptosis. Since rottlerin can sensitize Bcl-2- or Bcl-xL-overexpressing glioma cells but not human astrocytes to TRAIL-induced apoptosis, this combined treatment may offer an attractive strategy for safely treating resistant gliomas.
 ...
PMID:Rottlerin sensitizes glioma cells to TRAIL-induced apoptosis by inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP. 1553 13

Although protein kinase C (PKC) has been widely implicated in the positive and negative control of proliferation, the underlying cell cycle mechanisms regulated by individual PKC isozymes are only partially understood. In this report, we show that PKCdelta mediates phorbol ester-induced G1 arrest in lung adenocarcinoma cells and establish an essential role for this novel PKC in controlling the expression of the cell cycle inhibitor p21. Activation of PKC with phorbol 12-myristate 13-acetate (PMA) in early G1 phase impaired progression of lung adenocarcinoma cells into S phase, an effect that was completely abolished by specific depletion of PKCdelta, but not PKCalpha. Although the PKC effect was unrelated to the inhibition of cyclin D1 expression, PKC activation significantly up-regulated p21 and down-regulated Rb hyperphosphorylation and cyclin A expression. Elevations in p21 mRNA and protein by PMA were mediated by PKCdelta but not PKCalpha. Studies using luciferase reporters also revealed an essential role for PKCdelta in the PMA-induced inhibition of Rb-dependent cyclin A promoter activity. Finally, we showed that the cell cycle inhibitory effect of PKCdelta is greatly attenuated by RNA interference-mediated knock-down of p21. Our results identify a novel link between PKCdelta and G1 arrest via p21 up-regulation and highlight the complexities in the downstream effectors of PKC isozymes in the context of cell cycle progression and proliferation.
 ...
PMID:Phorbol ester-induced G1 phase arrest selectively mediated by protein kinase Cdelta-dependent induction of p21. 1605 35

TIS21(/BTG2/PC3), orthologs of mouse, human and rat, respectively, is initially identified as one of the early growth response genes and induced by various stimulations. TIS21 belongs to antiproliferative (APRO) gene family containing the BTG-Box A (Y(50)-N(71)) and BTG-Box B (L(97)-E(115)), which are highly conserved among various species. On the other hand, it has lately been found that the expression of TIS21 is constitutive and high in thymus, lung alveolar epithelium, proximal tubule of kidney and basal cell layer of prostate acini. Potential roles of TIS21 have been suggested as transcriptional co-regulator, differentiation and antiapoptotic factor in neurogenesis, key mediator of the stage-specific expansion of thymocyte and negative regulator of hematopoietic progenitor expansion, and tumor suppressor gene in both mouse and human. In addition, as pan-cell cycle regulator TIS21 induces G1/S arrest by pRB dependently and pRB independently and G2/M arrest and cell death in the p53 null tumor cells, and regulates the development of vertebrate patterning in mouse, paraxial mesoderm development in zebrafish, and notochord development in Xenopus. It has been known that the expression of TIS21 depends on the induction of wt p53 when cells are damaged, however, it can also be upregulated p53 independently by the activation of PKC-delta pathway in tumor cells. The characteristic roles of TIS21 are discussed in the present review: (1) TIS21 inhibits early phase of carcinogenesis in its high expressers such as kidney, prostate, breast and thymus: Loss of constitutive and high expression of TIS21 was observed in the precancerous lesions as well as tumor tissues. As an endogenous cell death molecule, TIS21 may be involved in translocation of Pin-1 to cytoplasm. Pin-1 subsequently interacts with Serine(147) residue in TIS21 protein, resulting in mitochondrial depolarization. (2) TIS21 regulates transition of cell cycle at G1/S and G2/M phases in cancer cells with inactive pRB and/or p53, as well as in normal cells by regulating pRB/p16(INK4a) pathway. The latter has already been well elucidated; TIS21 inhibits the expression of cyclin D1, thus resulting in the arrest of cells at G1/S phase by pRB and p53 dependent manner. On the other hand, TIS21 inhibits degradations of cyclin A and cyclin B1 at G2/M phase, and directly binds to Cdc2, resulting in the failure of mitotic exit and then increasing the tumor cell death, when stimulated by high concentration of EGF. Therefore, TIS21 can be suggested as a pan-cell cycle modulator. (3) TIS21 regulates embryo development by activating BMP signal through interaction with Smad 1 and Smad 8, thereby regulating vertebral patterning in mice. It is also involved in notochord development in Xenopus and paraxial mesoderm development in zebrafish. Based on the previous report that the expression of TIS21 is involved in the induction of senescence after chemotherapy of cancer cells, which can be a mechanism to resist carcinogenesis, TIS21(/BTG2/PC3), the endogenous cell death molecule and pan-cell cycle regulator, might be a link between cellular senescence and carcinogenesis.
 ...
PMID:TIS21 (/BTG2/PC3) as a link between ageing and cancer: cell cycle regulator and endogenous cell death molecule. 1645 75

E2F factors modulate a plethora of cell functions, including proliferation, differentiation, DNA repair and apoptosis. We have shown that differentiation in primary epidermal keratinocytes leads to E2F1 downregulation via activation of protein kinase C and p38 mitogen-activated protein kinase. We now demonstrate that E2F1 downregulation in differentiating keratinocytes involves its ubiquitination, as well as proteasomal degradation subsequent to CRM1-dependent nuclear export. E2F1 nuclear export specifically in response to differentiation requires regions adjacent to the cyclin A-binding domain in the N-terminus of this protein. Significantly, inhibition of p38 interferes with nuclear export and degradation of E2F1 during differentiation, but has no effect on E2F1 in undifferentiated cells. Thus, induction of differentiation in epidermal keratinocytes activates a specific program for post-transcriptional downregulation of E2F1, which involves signaling through p38 and activation of nuclear export pathways.
 ...
PMID:Activation of p38- and CRM1-dependent nuclear export promotes E2F1 degradation during keratinocyte differentiation. 1692 38

Transforming growth factor beta (TGFbeta), a multifunctional cytokine associated with vascular injury, is a potent inhibitor of cell proliferation. The current results demonstrate that the TGFbeta-induced growth arrest of vascular smooth muscle cells (VSMCs) is associated with cyclin A downregulation. TGFbeta represses the cyclin A gene through a cyclic AMP (cAMP) response element, which complexes with the cAMP response element binding protein (CREB). The CREB-cyclin A promoter interaction is hindered by TGFbeta, preceded by a TGFbeta receptor-dependent CREB phosphorylation. Induction of CREB phosphorylation with forskolin or 6bnz-cAMP mimics TGFbeta's inhibitory effect on cyclin A expression. Conversely, inhibition of CREB phosphorylation with a CREB mutant in which the phosphorylation site at serine 133 was changed to alanine (CREB-S133A) upregulated cyclin A gene expression. Furthermore, the CREB-S133A mutant abolished TGFbeta-induced CREB phosphorylation, cyclin A downregulation, and growth inhibition. Since we have previously shown that the novel PKC isoform protein kinase C delta (PKCdelta) is activated by TGFbeta in VSMCs, we tested the role of this kinase in CREB phosphorylation and cyclin A downregulation. Inhibition of PKCdelta by a dominant-negative mutant or by targeted gene deletion blocked TGFbeta-induced CREB phosphorylation and cyclin A downregulation. Taken together, our data indicate that phosphorylation of CREB stimulated by TGFbeta is a critical step leading to the inhibition of cyclin A expression and, thus, VSMC proliferation.
 ...
PMID:Phosphorylation of the cyclic AMP response element binding protein mediates transforming growth factor beta-induced downregulation of cyclin A in vascular smooth muscle cells. 1732 33

HuR is predominantly nuclear but following exposure to stress and mitogens, it can translocate to the cytoplasm where it stabilizes target mRNAs and/or modulates their translation. Several phosphorylation sites in a central 'hinge" region of HuR have been reported to affect its nucleocytoplasmic shuttle: phosphorylation by PKC at serine (S)221 and by Cdk1 at S202. Here, we investigated if there are additional putative phosphorylation sites within the HuR hinge region capable of influencing its cytoplasmic abundance. We systematically mutated all seven serine residues within the shuttling hinge domain to the nonphosphorylatable residue alanine (A), S197A, S202A, S221A, S229A, S232A, S241A and S242A. Using HeLa cells as the study system, we found that the HuR(S242A) mutant was more abundant in the cytoplasm in both untreated cells and in cells treated with short-wavelength ultraviolet light or with an inhibitor of Cdk1. Conversely, mutation of S242 to aspartic acid (D), rendered the phosphomimetic HuR(S242D) nuclear under all treatment conditions. S242 mutations did not influence HuR stability, but HuR(S242A) showed increased association with target cyclin A2 and cyclin B1 mRNAs. Accordingly, expression of HuR(S242A) led to increased cyclin mRNA stability and heightened cell proliferation rates. Our findings suggest that HuR phosphorylation at S242 hinders its cytoplasmic localization, its function as a posttranscriptional regulator, and its proliferative influence.
 ...
PMID:Modification at HuR(S242) alters HuR localization and proliferative influence. 1894 43

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder maintained by cancer stem cells. To target this population, we investigated the mechanism of action of BMS-214662, developed as a farnesyl transferase inhibitor (FTI) and unique in inducing apoptosis in these cells. By contrast, a related congener and equally effective FTI, BMS-225975 does not induce apoptosis, indicating a novel mechanism of action. BMS-214662 significantly and selectively induced apoptosis in primitive CD34(+)38(-) CML compared with normal cells. Apoptosis proceeded via the intrinsic pathway: Bax conformational changes, loss of mitochondrial membrane potential, generation of reactive oxygen species, release of cytochrome c, and caspase-9/3 activation were noted. Up-regulation of protein kinase Cbeta (PKCbeta), down-regulation of E2F1, and phosphorylation of cyclin A-associated cyclin-dependent kinase 2 preceded these changes. Cotreatment of CML CD34(+) and CD34(+)38(-) cells with PKC modulators, bryostatin-1, or hispidin markedly decreased these early events and the subsequent apoptosis. None of these events was elicited by BMS-214662 in normal CD34(+) cells or by BMS-225975 in CML CD34(+) cells. These data suggest that BMS-214662 selectively elicits a latent apoptotic pathway in CML stem cells that is initiated by up-regulation of PKCbeta and mediated by Bax activation, providing a molecular framework for development of novel therapeutics.
 ...
PMID:BMS-214662 induces mitochondrial apoptosis in chronic myeloid leukemia (CML) stem/progenitor cells, including CD34+38- cells, through activation of protein kinase Cbeta. 1973 29

Phorbol 12-myristate 13-acetate (PMA) is known to activate protein kinase C (PKC) and increase angiogenesis in cultured endothelial cells. Using a microRNA (miRNA) array, we found that PMA induced miR-146a expression in human microvascular endothelial cells. The miR-146a expression was dependent on dose and time and independent of PKC activation. Using a combined approach involving predictions using miRanda algorithm and whole genome microarray experiments with or without inhibition of miR-146a expression by LNA-antimir-146a or LNA-control, 29 potential target genes of miR-146a were identified. Because endothelial cell S phase progression is an early event in the induction of angiogenesis, we evaluated 5 cell cycle-related genes from the 29 target genes and found that the transcripts of 3 genes (CCNA2, PA2G4, and BRCA1) were downregulated after PMA treatment, but their expression was rescued upon miR-146a inhibition. However, inhibition of miR-146a expression failed to alter the cell cycle distribution or angiogenesis induced by PMA treatment. By using a combined approach involving computational prediction and a whole genome microarray experiment in the presence or absence of antimir, the observations in this presented article raise the possibility that antimir strategies might be used to identify the potential miRNA targets.
 ...
PMID:Identification of the potential target genes of microRNA-146a induced by PMA treatment in human microvascular endothelial cells. 1994 95


<< Previous 1 2 3 4 Next >>