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)

We found that many spontaneous human tumors exhibit increased levels of endocellular diacylglycerol (DAG) which is synthesized de novo as a byproduct of glycolysis. It has been shown that DAG mimics phorbol esters as a full tumor promoter in mouse skin carcinogenesis. A short term DAG treatment activates protein kinase C (PKC), while a long term "chronic" treatment down-regulates PKC. We show here that chronic treatment of human fibroblast with DAG induces p53 down-regulation and inhibition of p53 functional activity, and protection from UV-induced apoptosis. As PKC phosphorylation is necessary for p53 functional activity, we propose that chronic DAG treatment mimics the same event occurring in vivo for the effect of glycolysis in tumor progression.
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PMID:Chronic treatment of human fibroblasts cultures with diacylglycerol induces down-regulation of p53 functional activity. 970 61

1. The possible mechanisms of the antiproliferative and apoptotic effects of curcumin (diferuloylmethane), a polyphenol in the spice turmeric, on vascular smooth muscle cells were studied in rat aortic smooth muscle cell line (A7r5). 2. The proliferative response was determined from the uptake of [3H]-thymidine. Curcumin (10(-6)-10(-4) M) inhibited serum-stimulated [3H]-thymidine incorporation of both A7r5 cells and rabbit cultured vascular smooth muscle cells in a concentration-dependent manner. Cell viability, as determined by the trypan blue dye exclusion method, was unaffected by curcumin at the concentration range 10(-6) to 10(-5) M in A7r5 cells. However, the number of viable cells after 10(-4) M curcumin treatment was less than the basal value (2 x 10(5) cells). 3. To analyse the various stages of the cell cycle, [3H]-thymidine incorporation into DNA was determined every 3 h. After stimulation with foetal calf serum, quiescent A7r5 cells started DNA synthesis in 9 to 12 h (G1/S phase), then reached a maximum at 15 to 18 h (S phase). Curcumin (10(-6)-10(-4) M) added during either the G1/S phase or S phase significantly inhibited [3H]-thymidine incorporation. 4. Following curcumin (10(-6)-10(-4) M) treatment, cell cycle analysis utilizing flow cytometry of propidium iodide stained cells revealed a G0/G1 arrest and a reduction in the percentage of cells in S phase. Curcumin at 10(-4) M also induced cell apoptosis. It is suggested that curcumin arrested cell proliferation and induced cell apoptosis, and hence reduced the [3H]-thymidine incorporation. 5. The apoptotic effect of 10(-4) M curcumin was also demonstrated by haematoxylin-eosin staining, TdT-mediated dUTP nick end labelling (TUNEL), and DNA laddering. Curcumin (10(-4) M) induced cell shrinkage, chromatin condensation, and DNA fragmentation. 6. The membranous protein tyrosine kinase activity stimulated by serum in A7r5 cells was significantly reduced by curcumin at the concentration range 10(-5) to 10(-4) M. On the other hand, the cytosolic protein kinase C activity stimulated by phorbol ester was reduced by 10(-4) M curcumin, but unaffected by lower concentrations (10(-6)-10(-5) M). 7. The levels of c-myc, p53 and bcl-2 mRNA were analysed using a reverse transcription-polymerase chain reaction (RT-PCR) technique. The level of c-myc mRNA was significantly reduced by curcumin (10(-5)-10(-4) M) treatment. And, the level of bcl-2 mRNA was significantly reduced by 10(-4) M curcumin. However, the alteration of the p53 mRNA level by curcumin (10(-5)-10(-4) M) treatment did not achieve significance. The effects of curcumin on the levels of c-myc and bcl-2 mRNA were then confirmed by Northern blotting. 8. Our results demonstrate that curcumin inhibited cell proliferation, arrested the cell cycle progression and induced cell apoptosis in vascular smooth muscle cells. Curcumin may be useful as a template for the development of drugs to prevent the pathological changes of atherosclerosis and post-angioplasty restenosis. Our results suggest that the antiproliferative effect of curcumin may partly be mediated through inhibition of protein tyrosine kinase activity and c-myc mRNA expression. And, the apoptotic effect may partly be mediated through inhibition of protein tyrosine kinase activity, protein kinase C activity, c-myc mRNA expression and bcl-2 mRNA expression.
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PMID:Effect of curcumin on cell cycle progression and apoptosis in vascular smooth muscle cells. 972 Jul 70

Phosphorylation of the tumor suppressor p53 is generally thought to modify the properties of the protein in four of its five independent domains. We used synthetic peptides to directly study the effects of phosphorylation on the non-sequence-specific DNA binding and conformation of the C-terminal, basic domain. The peptides corresponded to amino acids 361-393 and were either nonphosphorylated or phosphorylated at the protein kinase C (PKC) site, Ser378, or the casein kinase II (CKII) site, Ser392, or bis-phosphorylated on both the PKC and the CKII sites. A fluorescence polarization analysis revealed that either the recombinant p53 protein or the synthetic peptides bound to two unrelated target DNA fragments. Phosphorylation of the peptide at the PKC or the CKII sites clearly decreased DNA binding, and addition of a second phosphate group almost completely abolished binding. Circular dichroism spectroscopy showed that the peptides assumed identical unordered structures in aqueous solutions. The unmodified peptide, unlike the Ser378 phosphorylated peptide, changed conformation in the presence of DNA. The inherent ability of the peptides to form an alpha-helix could be detected when circular dichroism and nuclear magnetic resonance spectra were taken in trifluoroethanol-water mixtures. A single or double phosphorylation destabilized the helix around the phosphorylated Ser378 residue but stabilized the helix downstream in the sequence.
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PMID:Phosphorylation of the C-terminal sites of human p53 reduces non-sequence-specific DNA binding as modeled with synthetic peptides. 975 64

Although almost all pituitary tumors are benign adenomas, a surprisingly large number of these tumors invade tissues outside of the pituitary gland. Such invasion, by itself, is not diagnostic of pituitary carcinomas, which are exceedingly rare (0.13% of 2,342 pituitary tumors in one series). Several different criteria are available to determine whether a tumor is invasive. Intraoperative biopsies demonstrate an 85% incidence of microscopic invasion of the dura. Evidence of gross invasion at surgery and radiologic evidence of invasion on magnetic resonance imaging (MRI) and computed tomographic (CT) scans occur at a much lower incidence but may be more predictive of surgical cure. Invasive adenomas also have higher proliferation rates than do noninvasive adenomas, as shown by immunohistochemical detection of proliferating cell nuclear antigen (PCNA), Ki-67, and MIB-1. The expression of p53, increased epidermal growth factor receptors, and protein kinase C activity also correlate with invasion and aggressive behavior. Clinically significant invasion is more frequent with macroadenomas. Macroadenomas of all pituitary tumor subtypes except gonadotroph macroadenomas have a greater than 50% incidence of gross invasion. Currently, there is no accepted means of predicting an adenoma's clinically significant invasiveness and long-term aggressiveness.
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PMID:Aggressive pituitary tumors. 977 77

In many malignant cells, both the anchorage requirement for survival and the function of the p53 tumor suppressor gene are subverted. These effects are consistent with the hypothesis that survival signals from extracellular matrix (ECM) suppress a p53-regulated cell death pathway. We report that survival signals from fibronectin are transduced by the focal adhesion kinase (FAK). If FAK or the correct ECM is absent, cells enter apoptosis through a p53-dependent pathway activated by protein kinase C lambda/iota and cytosolic phospholipase A2. This pathway is suppressible by dominant-negative p53 and Bcl2 but not CrmA. Upon inactivation of p53, cells survive even if they lack matrix signals or FAK. This is the first report that p53 monitors survival signals from ECM/FAK in anchorage- dependent cells.
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PMID:Extracellular matrix survival signals transduced by focal adhesion kinase suppress p53-mediated apoptosis. 978 62

We have evaluated the effects of bryostatin 1 on growth of a highly malignant p53-null mouse mammary tumor line, 4T1, and the mechanism by which bryostatin 1 inhibits in vitro growth and in vivo development of tumor and metastases from the orthotopic site. Bryostatin 1 at 20-400 nM concentrations inhibits growth of 4T1 cells by approximately 60% in two-day cultures. Inhibition of growth is associated with an increase in the number of cells undergoing apoptosis with concomitant elevation in the steady state levels of bax protein and drop in bcl-2 levels. The cytotoxic effect of bryostatin 1 on 4T1 cells occurs independently of p53, since there was no evidence of p53-mediated transcriptional activity in 4T1 cells following treatment with bryostatin 1.4T1 cells respond in vivo to bryostatin 1 therapy (75 microg/kg body weight). Intraperitoneal administration of bryostatin 1 inhibits both primary and secondary tumor growth by approximately 50%. However, although bryostatin 1 has a remarkable capacity to slow tumor growth and progression, it is unable to completely eradicate tumor growth and progression due to in vivo development of tumor resistance to bryostatin 1. Levels and cellular distribution of PKCalpha and delta do not correlate with the growth inhibitory effects of bryostatin 1 on 4T1 cells; however, reduction in cytosolic PKCalpha and delta without associated increase in membrane compartment appear to correlate with bryostatin-resistance. Our results suggest that the therapeutic effects of bryostatin 1 in our system do not involve alterations in levels and distribution of PKC but rather a direct upregulation of bax/ bcl-2 ratios that is independent of p53.
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PMID:p53 and protein kinase C independent induction of growth arrest and apoptosis by bryostatin 1 in a highly metastatic mammary epithelial cell line: In vitro versus in vivo activity. 985 25

In this study, we first demonstrated that the widely used oral antifungal drug, ketoconazole (KT), can induce apoptosis in various type of human cancer cells and in a primary culture of rat liver cells. We further investigated the molecular mechanisms of KT-induced apoptosis. It was found that KT induced nuclear accumulation of p53 protein in a dose- and time-dependent manner. The level of p53 protein was elevated approximately three times as much in treated cells 24 h after KT (5 microM) exposure as in cells receiving mock treatment. We found that cells containing wild-type p53 (COLO 205 and Hep G2) were more sensitive to KT exposure. The bax protein was induced and the bcl-2 protein was inhibited by KT in cells containing wild-type p53 (Hep G2, COLO 205) but not in cells without p53 (Hep 3B). The caspase-3 was activated 24 h after KT treatment. The Poly-(ADP ribose) polymerase (PARP) and the lamin A degradation was induced by KT, which promoted nuclear membrane disassembly and eventually caused apoptosis. Our results also indicated that none of the PKC gene family was involved in KT-induced apoptosis.
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PMID:Ketoconazole-induced apoptosis through P53-dependent pathway in human colorectal and hepatocellular carcinoma cell lines. 987 98

p21(WAF1) inhibits cyclin-cyclin-dependent kinase (Cdk) complexes, causing cell cycle arrest. p21(WAF1) contains p53-binding sites in its promoter and expression of p21(WAF1) is induced by functional p53. In the present work, we have studied the role of protein kinase C (PKC) in the induction of p21(WAF1) and show that induction of p21(WAF1) expression can occur by activation of PKC in cells having no p53. Human ovarian carcinoma cells, SKOV-3, lack p53 protein and PMA, a potent activator of PKC, did not induce p53. PMA increased the expression of p21(WAF1) mRNA both in these cells and in other cells which do not contain p53 (THP-1 and U937). Treatment of human embryonic fibroblasts, WI38, with PMA also induced the accumulation of p21(WAF1) without affecting p53 levels. However, PMA did not increase levels of p21(WAF1) mRNA in cells where either the PKC or the mitogen-activated protein kinase pathway was blocked. Furthermore, treatment of cells with various phorbol ester derivatives which activate PKC resulted in the induction of p21(WAF1) in SKOV-3 cells. In contrast, phorbol esters which do not activate PKC failed to induce p21(WAF1) expression. PMA increased the transcriptional rate of p21(WAF1) and activated the transcription of a luciferase reporter gene, controlled by the p21 promoter, in SKOV-3 cells with or without a p53 consensus-binding sequence. By contrast, PMA markedly stabilized p21(WAF1) mRNA; the half-life (t1/2) of p21(WAF1) in PMA-treated cells was >8 h compared with <1 h in untreated cells. These findings provide evidence that the PKC pathway induces expression of p21(WAF1) independently of p53. Our present study also suggests that the accumulation of p21(WAF1) transcripts by PMA occurs mainly at post-transcriptional level.
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PMID:p21WAF1 expression by an activator of protein kinase C is regulated mainly at the post-transcriptional level in cells lacking p53: important role of RNA stabilization. 989 8

Analysis of the expression of a number of known genes in cultured human cells has revealed UVB-induced changes that may be specific for melanocytic cells. The response of c-fos, p53 and HIV-LTR reporter constructs to UVB and UVC was reduced in MM96L melanoma cells compared to HeLa. Cell cycle arrest produced by UVA, gamma radiation, cisplatin or the antimetabolite deoxyinosine differed from that of UVB. Cell cycle analysis after multiple doses of UVB raised the possibility that UVB-induced pRb depletion could result in increased mutation and thus enhanced tumourigenesis of irradiated melanocytes in skin subjected to a defined pattern of UVB exposure. To extend the analysis of gene expression in cultured melanocytic cells to uncharacterised genes, promoter trap cell clones containing unknown genes 'tagged' by a beta-galactosidase reporter construct were generated from MM96L cells. Altered gene expression in clones treated with a panel of DNA-damaging agents was quantitated by measurement of beta-galactosidase activity. Of the clones containing 'tagged' endogenous promoters induced by UVB, 52% were induced only by UVB and not by other DNA-damaging agents (cisplatin, N-methyl-N-nitro-nitrsoguanidine, fotemustine). One third of the clones were also activated by TPA suggesting that general DNA damage responses involving PKC are activated less frequently than unique pathways of gene activation. Overall, 60% of the 50 clones that responded to the panel of agents were induced by only one of the agents, indicating that a high proportion of genes are induced by agent-specific mechanisms. In the long term, promoter trapping may allow the full repertoire of UVB-inducible genes to be characterised.
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PMID:UVB-specific regulation of gene expression in human melanocytic cells: cell cycle effects and implication in the generation of melanoma. 992 Apr 26

The effect of serum starvation on the expression and phosphorylation of PKC-alpha and p53 in Chinese hamster V79 cells was investigated. Serum starvation led to growth arrest, rounding up of cells and the appearance of new PKC-alpha and p53 bands on Western blots. Prolonged incubation (> or = 48 hr) in serum-deprived medium led to cell detachment and death. Moving cells to fresh medium containing 10% serum before, but not after, cell detachment reversed the changes observed in PKC-alpha and p53, and also prevented later cell detachment. Radiolabelling studies showed that the higher-molecular-weight PKC-alpha and p53 bands result from increased phosphorylation, while a lower-molecular-weight PKC-alpha band reflects newly synthesized protein. Immunocomplex kinase assays have shown that the increased phosphorylation of PKC-alpha is associated with its increased activity. To study the relationship between PKC-alpha, p53 and cell death, cells were treated either with TPA, to down-regulate PKC or with staurosporine, to inhibit PKC activity. Staurosporine, a potent PKC inhibitor and inducer of programmed cell death, caused the appearance of new PKC-alpha and p53 bands similar to those induced by serum starvation. If serum starvation was preceded by prolonged (48 hr) TPA treatment to down-regulate PKC-alpha, cell detachment and death did not take place within the same time frame. Intracellular fractionation of cells demonstrated that increased expression of PKC-alpha and the appearance of the associated higher and lower molecular-weight bands occurred in the nucleus. These data highlight the association of PKC-alpha and p53 with cellular events leading to cell death.
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PMID:Effect of serum starvation on expression and phosphorylation of PKC-alpha and p53 in V79 cells: implications for cell death. 993 81


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