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 small molecule UCN-01 is a cyclin-dependent kinase (CDK) modulator shown to have antiproliferative effects against several in vitro and in vivo cancer models currently being tested in human clinical trials. Although UCN-01 may inhibit several serine-threonine kinases, the exact mechanism by which it promotes cell cycle arrest is still unclear. We have reported previously that UCN-01 promotes G(1)-S cell cycle arrest in a battery of head and neck squamous cancer cell lines. The arrest is accompanied by an increase in both p21(waf1/cip1) and p27(kip1) CDK inhibitors leading to loss in G(1) CDK activity. In this report, we explore the role and the mechanism for the induction of these endogenous CDK inhibitors. We observed that p21 was required for the cell cycle effects of UCN-01, as HCT116 lacking p21 (HCT116 p21(-/-)) was refractory to the cell cycle effects of UCN-01. Moreover, UCN-01 promoted the accumulation of p21 at the mRNA level in the p53-deficient HaCaT cells without increase in the p21 mRNA half-life, suggesting that UCN-01 induced p21 at the transcriptional level. To study UCN-01 transcriptional activation of p21, we used several p21(waf1/cip1) promoter-driven luciferase reporter plasmids and observed that UCN-01 activated the full-length p21(waf1/cip1) promoter and a construct lacking p53 binding sites. The minimal promoter region required for UCN-01 (from -110 bp to the transcription start site) was the same minimal p21(waf1/cip1) promoter region required for Ras enhancement of p21(waf1/cip1) transcription. Neither protein kinase C nor PDK1/AKT pathways were relevant for the induction of p21 by UCN-01. In contrast, the activation of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase mitogen-activated protein kinase pathways was required for p21 induction as UCN-01 activated this pathway, and genetic or chemical MEK inhibitors blunted p21 accumulation. These results demonstrated for the first time that p21 is required for UCN-01 cell cycle arrest. Moreover, we showed that the accumulation of p21 is transcriptional via activation of the MEK pathway. This novel mechanism, by which UCN-01 exerts its antiproliferative effect, represents a promising strategy to be exploited in future clinical trials.
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PMID:UCN-01-induced cell cycle arrest requires the transcriptional induction of p21(waf1/cip1) by activation of mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway. 1515 Jan 22

Expression of a dominant negative atypical protein kinase C (aPKC), PKCzeta, prevents nuclear translocation of extracellular regulated kinase 2 (ERK-2), p27 nuclear reduction, and DNA synthesis induced by estradiol in human mammary cancer-derived MCF-7 cells. aPKC action upstream of these events has been analyzed. In hormone-stimulated NIH 3T3 and Cos cells ectopically expressing human estrogen receptor alpha (hERalpha), aPKC is activated by phosphatidylinositol 3-kinase (PI 3-kinase) and, in turn, controls the Ras/MEK-1/ERK cascade. In MCF-7 and Cos cells stimulated by hormone, PI 3-kinase activates PKCzeta by Thr410 phosphorylation. Serine phosphorylation of PKCzeta is simultaneously induced. PKCzeta activation leads to recruitment of Ras to a multimolecular complex that also includes hERalpha, Src, PI 3-kinase, and aPKC. We propose that PKCzeta pushes Ras and the signaling complex close together in such a way that it facilitates the Src-dependent Ras activation. This activation is crucial for the interplay between estradiol-triggered signaling and cell cycle machinery.
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PMID:Role of atypical protein kinase C in estradiol-triggered G1/S progression of MCF-7 cells. 1531 72

Several genes are regulated by tocopherols which can be categorized, based on their function, into five groups: genes that are involved in the uptake and degradation of tocopherols (Group 1) include alpha-tocopherol transfer protein (alpha-TTP) and cytochrome P450 (CYP3A); genes that are associated with lipid uptake and atherosclerosis (Group 2) include CD36, SR-BI and SR-AI/II. Genes that modulate the expression of extracellular proteins (Group 3) include tropomyosin, collagen(alpha1), MMP-1, MMP-19 and connective tissue growth factor (CTGF). Genes that are related to inflammation, cell adhesion and platelet aggregation (Group 4) include E-selectin, ICAM-1, integrins, glycoprotein IIb, II-2, IL-4 and IL-beta. Group 5 comprises genes coding for proteins involved in cell signaling and cell cycle regulation and consists of PPAR-gamma, cyclin D1, cyclin E, Bcl2-L1, p27 and CD95 (Apo-1/Fas ligand). The expression of P27, Bcl2, alpha-TTP, CYP3A, tropomyosin, II-2, PPAR-gamma, and CTGF appears to be up-regulated by one or more tocopherols whereas all other listed genes are down-regulated. Several mechanisms may underlie tocopherol-dependent gene regulation. In some cases protein kinase C has been implicated due to its deactivation by alpha-tocopherol and its participation in the regulation of a number of transcription factors (NF-kappaB, AP-1). In other cases a direct involvement of PXR/RXR has been documented. The antioxidant responsive element (ARE) appears in some cases to be involved as well as the transforming growth factor beta responsive element (TGF-beta-RE). This heterogeneity of mediators of tocopherol action suggests the need of a common element that could be a receptor or a co-receptor, able to interact with tocopherol and with transcription factors directed toward specific regions of promoter sequences of sensitive genes. Here we review recent results of the search for molecular mechanisms underpinning the central signaling mechanism.
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PMID:Regulation of gene expression by alpha-tocopherol. 1531 6

8-Chloro-cyclic AMP (8-Cl-cAMP) is known to be most effective in inducing growth inhibition and differentiation of a number of cancer cells. Also, its cellular metabolite, 8-Cl-adenosine was shown to induce growth inhibition in a variety of cell lines. However, the signaling mechanism that governs the effects of 8-Cl-cAMP and/or 8-Cl-adenosine is still uncertain and it is not even sure which of the two is the key molecule that induces growth inhibition. In this study using mouse fibroblast DT cells, it was found that adenosine kinase inhibitor and adenosine deaminase could reverse cellular growth inhibition induced by 8-Cl-cAMP and 8-Cl-adenosine. And 8-Cl-cAMP could not induce growth inhibition in the presence of phosphodiesterase (PDE) inhibitor, but 8-Cl-adenosine could. We also found that protein kinase C (PKC) inhibitor could restore this growth inhibition, and both the 8-Cl-cAMP and 8-Cl-adenosine could activate the enzymatic activity of PKC. Besides, after 8-Cl-cAMP and 8-Cl-adenosine treatment, cyclin B was down-regulated and a CDK inhibitor, p27 was up-regulated in a time-dependent manner. These results suggest that it is not 8-Cl-cAMP but 8-Cl-adenosine which induces growth inhibition, and 8-Cl-cAMP must be metabolized to exert this effect. Furthermore, there might exist signaling cascade such as PKC activation and cyclin B down-regulation after 8-Cl-cAMP and 8-Cl-adenosine treatment.
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PMID:8-Cl-cAMP and its metabolite, 8-Cl-adenosine induce growth inhibition in mouse fibroblast DT cells through the same pathways: protein kinase C activation and cyclin B down-regulation. 1533 62

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.
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PMID:Epidermal growth factor receptor-dependent regulation of integrin-mediated signaling and cell cycle entry in epithelial cells. 1536 78

alpha-Tocopherol modulates two major signal transduction pathways centered on protein kinase C and phosphatidylinositol 3-kinase. Changes in the activity of these key kinases are associated with changes in cell proliferation, platelet aggregation, and NADPH-oxidase activation. Several genes are also regulated by tocopherols partly because of the effects of tocopherol on these two kinases, but also independently of them. These genes can be divided in five groups: Group 1. Genes that are involved in the uptake and degradation of tocopherols: alpha-tocopherol transfer protein, cytochrome P450 (CYP3A), gamma-glutamyl-cysteine synthetase heavy subunit, and glutathione-S-transferase. Group 2. Genes that are implicated with lipid uptake and atherosclerosis: CD36, SR-BI, and SR-AI/II. Group 3. Genes that are involved in the modulation of extracellular proteins: tropomyosin, collagen-alpha-1, MMP-1, MMP-19, and connective tissue growth factor. Group 4. Genes that are connected to adhesion and inflammation: E-selectin, ICAM-1 integrins, glycoprotein IIb, IL-2, IL-4, IL-1b, and transforming growth factor-beta (TGF-beta). Group 5. Genes implicated in cell signaling and cell cycle regulation: PPAR-gamma, cyclin D1, cyclin E, Bcl2-L1, p27, CD95 (APO-1/Fas ligand), and 5a-steroid reductase type 1. The transcription of p27, Bcl2, alpha-tocopherol transfer protein, cytochrome P450 (CYP3A), gamma-glutamyl-cysteine sythetase heavy subunit, tropomyosin, IL-2, and CTGF appears to be upregulated by one or more tocopherols. All the other listed genes are downregulated. Gene regulation by tocopherols has been associated with protein kinase C because of its deactivation by alpha-tocopherol and its contribution in the regulation of a number of transcription factors (NF-kappaB, AP1). A direct participation of the pregnane X receptor (PXR) / retinoid X receptor (RXR) has been also shown. The antioxidant-responsive element (ARE) and the TGF-beta-responsive element (TGF-beta-RE) appear in some cases to be implicated as well.
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PMID:Vitamin E mediates cell signaling and regulation of gene expression. 1575 36

PKC-delta is a serine/threonine kinase that mediates diverse signal transduction pathways. We previously demonstrated that overexpression of PKC-delta slowed the G1 progression of Caco-2 colon cancer cells, accelerated apoptosis, and induced cellular differentiation. In this study, we further characterized the PKC-delta dependent signaling pathways involved in these tumor suppressor actions in Caco-2 cells overexpressing PKC-delta using a Zn2+ inducible expression vector. Consistent with a G1 arrest, increased expression of PKC-delta caused rapid and significant downregulation of cyclin D1 and cyclin E proteins (50% decreases, P<0.05), while mRNA levels remained unchanged. The PKC agonist, phorbol 12-myristate 13-acetate (TPA, 100 nM, 4 h), induced two-fold higher protein and mRNA levels of p21(Waf1), a cyclin-dependent kinase (cdk) inhibitor in PKC-delta transfectants compared with empty vector (EV) transfected cells, whereas the PKC-delta specific inhibitor rottlerin (3 microM) or knockdown of this isoenzyme with specific siRNA oligonucleotides blocked p21(Waf1) expression. Concomitantly, compared to EV control cells, PKC-delta upregulation decreased cyclin D1 and cyclin E proteins co-immunoprecipitating with cdk6 and cdk2, respectively. In addition, overexpression of PKC-delta increased binding of cdk inhibitor p27(Kip1) to cdk4. These alterations in cyclin-cdks and their inhibitors are predicted to decrease G1 cyclin kinase activity. As an independent confirmation of the direct role PKC-delta plays in cell growth and cell cycle regulation, we knocked down PKC-delta using specific siRNA oligonucleotides. PKC-delta specific siRNA oligonucleotides, but not irrelevant control oligonucleotides, inhibited PKC-delta protein by more than 80% in Caco-2 cells. Moreover, PKC-delta knockdown enhanced cell proliferation ( approximately 1.4-2-fold, P<0.05) and concomitantly increased cyclin D1 and cyclin E expression ( approximately 1.7-fold, P<0.05). This was a specific effect, as nontargeted PKC-zeta was not changed by PKC-delta siRNA oligonucleotides. Consistent with accelerated apoptosis in PKC-delta transfectants, compared to EV cells, PKC-delta upregulation increased proapoptotic regulator Bax two-fold at mRNA and protein levels, while antiapoptotic Bcl-2 protein was decreased by 50% at a post-transcriptional level. PKC-delta specific siRNA oligonucleotides inhibited Bax protein expression by more than 50%, indicating that PKC-delta regulates apoptosis through Bax. Taken together, these results elucidate two critical mechanisms regulated by PKC-delta that inhibit cell cycle progression and enhance apoptosis in colon cancer cells. We postulate these antiproliferative pathways mediate an important tumor suppressor function for PKC-delta in colonic carcinogenesis.
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PMID:Protein kinase C delta inhibits Caco-2 cell proliferation by selective changes in cell cycle and cell death regulators. 1643 69

EGF or TGFB1 alone stimulates but together attenuate granulosa cell DNA synthesis. Intact preantral follicles from hamsters were cultured with TGFB1, EGF, or both to reveal the mechanisms of such unique regulation. Follicular CCND2 (also known as cyclin D2), CDKN1B (also known as p27(kip1)), and the involvement of appropriate signaling intermediaries and kinases were examined. TGFB1, acting via SMAD2 and SMAD3, antagonized the degradation of CCND2 protein by blocking its phosphorylation. In contrast, TGFB1 supported CDKN1B degradation by involving MAPK14 (also known as p38 Map Kinase) and PKC, resulting in CDK4 activation and DNA synthesis. EGF via MAPK3/1 maintained functional levels of CCND2 through CCND2 synthesis as well as degradation. EGF and TGFB1 together inhibited CDK4 activation and DNA synthesis. EGF attenuated TGFB1 stimulated phosphorylation of SMAD3, TGFB1-induced activation of MAPK14 and PKC, and TGFB1 suppression of CCND2 degradation. In contrast, TGFB1 suppressed EGF-induced increase in CCND2 mRNA levels. The final outcome was CCND2 degradation without replenishment and decreased activities of MAPK14 and PKC leading to suppression of CDK4 activation. The results indicate that each growth factor involves a separate mechanism to maintain an effective level of CCND2 in granulosa cells for the activation of CDK4 and induction of DNA synthesis. However, their simultaneous action is inhibitory to follicular DNA synthesis because they counteract each other's activity by interfering at specific sites. Because both EGF and TGFB1 are present in granulosa cells, this mechanism may explain how their effects are temporally modulated for granulosa cell proliferation and folliculogenesis.
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PMID:Transforming growth factor B1 stimulated DNA synthesis in the granulosa cells of preantral follicles: negative interaction with epidermal growth factor. 1652 33

Ghrelin stimulates while somatostatin inhibits GH release and they thus serve as functional antagonists. We have compared their effects on cell proliferation. Ghrelin stimulates while somatostatin inhibits cell proliferation in most tissues and cell lines. Here we show that ghrelin and desoctanoyl ghrelin stimulate cell proliferation in rat pituitary cell line (GH3), and these effects could be inhibited with mitogen-activated protein kinase (MAPK), tyrosine kinase and protein kinase C inhibitors. Somatostatin and its analogs negatively regulate the growth of pituitary cells, and we now show that they inhibit MAPK activation. We hypothesised that one of the mechanisms involved in the somatostatin effect is a stimulation of cell cycle inhibitor p27, as pituitary adenomas have decreased p27 peptide content. Both octreotide and a new somatostatin analog SOM230 treatment resulted in an upregulation of p27 protein levels in human somatotrophinoma cells. In summary, we suggest that ghrelin and somatostatin have opposite effects on somatotroph cells not just at the level of GH release but also in terms of cell proliferation. Ghrelin may play a role in pituitary tumorigenesis via an autocrine/paracrine pathway. Our results also suggest that the antiproliferative effect of somatostatin analogs octreotide and SOM230 involve the up-regulation of p27 and down-regulation of the MAPK pathway in human somatotrophinomas.
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PMID:Novel molecular aspects of pituitary adenomas. 1662 55

Protein kinase C (PKC) is a family of serine-threonine kinases that regulate many cell processes. To study the role of PKCdelta in thyroid cancer cells, we used a replication-deficient adenovirus (PKCdeltaAdV), to tightly control PKCdelta expression. In NPA cells, activation of wild-type (WT) PKCdelta with phorbol 12-myristate 13-acetate (PMA) induced an arrest in cell growth at G(1) phase, which was itself inhibited by the PKCdelta inhibitor rottlerin. Furthermore, overexpression of a dominant negative PKCdelta did not induce G(1) arrest. These findings strongly suggested that PKCdelta induced cell growth arrest in NPA cells. We investigated the mechanism of G1 arrest by examining G(1)-related proteins and mitogen-activated protein kinase (MAPK) by Western blotting. After activation of WTPKCdelta with PMA, cyclin E expression and retinoblastoma protein (Rb) phosphorylation decreased; the expression of p27(Kip1) increased and the phosphorylation of extracellular signal-regulated kinase (ERK) MAPK decreased. These results indicated that the activation of PKCdelta induced cell growth arrest in NPA cells, through an ERK MAPK-p27(Kip1)-cyclin E-pRb pathway. PKCdelta may therefore be an effective molecular target for novel therapy in thyroid cancer.
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PMID:Activation of protein kinase C delta induces growth arrest in NPA thyroid cancer cells through extracellular signal-regulated kinase mitogen-activated protein kinase. 1664 78


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