Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of studies have shown that tamoxifen increases the sensitivity of several types of solid tumours to cisplatin without increasing the associated side effects. The cellular mechanisms responsible for this increased sensitivity are currently unknown. In this study we have investigated whether tamoxifen alone or in combination with cisplatin could induce apoptosis in head and neck squamous cell carcinoma (HNSCC) cell lines. We have shown that tamoxifen treatment resulted in G(1) arrest in two cell lines, HN5 and HN6. Tamoxifen induced growth suppression was independent of p53 status but resulted in up-regulation of cyclin dependent kinase inhibitors (CDKIs) p21/Waf-1, p27/Kip1 and p15/INK4a. Furthermore, tamoxifen treatment resulted in an increased level of hypophosphorylated active RB. Cisplatin induced p53 independent apoptosis in both head and neck cancer cell lines. There was a significant sensitizing effect of tamoxifen on cisplatin-induced apoptosis in HN5 and HN6 cells, with the combined treatment being more effective in inducing apoptosis. Addition of tamoxifen did not result in significant inhibition of PKC activity in HN5 and HN6 cells. However, tamoxifen treatment resulted in increased secretion of TGF-beta1 by HN5 and HN6 cells. An anti-TGF-beta blocking antibody prevented both the blockade of cellular proliferation and the increased expression of CDKIs associated with tamoxifen treatment of HN5 and HN6 cells. These results show that tamoxifen alone induces a transient G(1) arrest that greatly sensitizes the cells to apoptosis induced by cisplatin. We have shown that the mechanism for this p53-independent G(1) arrest and apoptosis is at least partly due to the activation of TGF-beta1 resulting in the induction of p15/INK4b, p27/Kip-1, p21/Waf-1 and RB hypophosphorylation. These in vitro results suggest that combination of tamoxifen and cisplatin might be a more effective treatment for head and neck cancers than single modality therapy.
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PMID:Tamoxifen inhibits the growth of head and neck cancer cells and sensitizes these cells to cisplatin induced-apoptosis: role of TGF-beta1. 1237 63

Human exposure to arsenic, a ubiquitous and toxic environmental pollutant, is associated with an increased incidence of skin cancer. However, the mechanism(s) associated with AsIII-mediated toxicity and carcinogenesis at low levels of exposure remains elusive. Aberrations in cell proliferation, oxidative damage, and DNA-repair fidelity have been implicated in sodium arsenite (AsIII)-mediated carcinogenicity and toxicity, but these events have been examined in isolation in the majority of biological models of arsenic exposure. We hypothesized that the simultaneous interaction of these effects may be important in arsenic-mediated neoplasia in the skin. To evaluate this, normal human epidermal keratinocytes (NHEK) were exposed to nontoxic doses (0.005-5 micro M) of AsIII and monitored for several physiological endpoints at the times when cells were harvested for gene expression measurements (1-24 h). Two-fluor cDNA microarray analyses indicated that AsIII treatment decreased the expression of genes associated with DNA repair (e.g., p53 and Damage-specific DNA-binding protein 2) and increased the expression of genes indicative of the cellular response to oxidative stress (e.g., Superoxide dismutase 1, NAD(P)H quinone oxidoreductase, and Serine/threonine kinase 25). AsIII also modulated the expression of certain transcripts associated with increased cell proliferation (e.g., Cyclin G1, Protein kinase C delta), oncogenes, and genes associated with cellular transformation (e.g., Gro-1 and V-yes). These observations correlated with measurements of cell proliferation and mitotic measurements as AsIII treatment resulted in a dose-dependent increase in cellular mitoses at 24 h and an increase in cell proliferation at 48 h of exposure. Data in this manuscript demonstrates that AsIII exposure simultaneously modulates DNA repair, cell proliferation, and redox-related gene expression in nontransformed, normal NHEK. It is anticipated that data in this report will serve as a foundation for furthering our knowledge of AsIII-regulated gene expression in skin and other tissues and contribute to a better understanding of arsenic toxicity and carcinogenesis.
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PMID:Coordination of altered DNA repair and damage pathways in arsenite-exposed keratinocytes. 1237 79

Butyrolactone I (BL) is a competitive inhibitor of ATP for binding and activation of cyclin-dependent kinases and is a potent inhibitor of cell cycle progression. Treatment of H460 human lung and SW480 human colon cancer cells with doses of BL that exceed the Ki for CDK inhibition but which are much lower than doses required to inhibit MAPK, PKA, PKC, or EGFR lead to a rapid significant reduction of endogenous p21 protein expression. BL-dependent inhibition of p21 expression appears to be p53-independent. BL-dependent p21 degradation was blocked by lactacystin, consistent with the hypothesis that there is accelerated p21 proteasomal degradation in the presence of BL. BL also inhibited the p53-dependent increase of p21 protein expression in cells exposed to the DNA damag-ing agent etoposide, and favored a greater G2/M arrest as compared to the non-BL exposed cells. BL accelerated the degradation of exogenously expressed p21 that was not observed with a C-terminal truncated form of p21. Degradation of exogenous p21 led to a shift to G2 accumulation in the cells exposed to BL. We conclude that BL has effects on the cell cycle beyond its role as a CDK inhibitor and can be used as a novel tool to study the mechanism of p21 degradation and the consequences towards p21- dependent checkpoints.
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PMID:The cyclin-dependent kinase inhibitor butyrolactone is a potent inhibitor of p21 (WAF1/CIP1 expression). 1242 18

The resistant problem is the main restriction factor for clinical usage of taxol. The main mechanism of its resistance includes the high expression of P-gp, beta- and alpha-tubulin isotypes, the alteration expression of PKC, Bcl-2, p53, and ErbB2. The reversing method includes the use of analogues of taxol to reduce the expression of P-gp, or the use of antibody, immunotoxin, antisence oligonucleotide, and liposomes. The combination with other drugs can also be a method to reverse the resistance of taxol.
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PMID:[Development of research for drug-resistance mechanism of taxol]. 1245 28

Activation of the tumor suppressor p53 after genotoxic insults may result in two different responses: growth arrest or apoptosis. In this study, we analysed how mitogenic stimulation of primary mouse lymphocytes influences p53 signaling upon gamma-irradiation. We found that G(0) lymphocytes rapidly went into p53-dependent apoptosis, whereas stimulated lymphocytes went into a p53-dependent, p21-mediated growth arrest. The switch in p53 response upon stimulation did neither result from a switch in transcriptional activation of major p53 target genes, nor from the high level of p21 expressed in stimulated, irradiated cells. Growth stimulation, however, led to the upregulation of the antiapoptotic factors Bcl-x(L) and Bfl-1. In resting cells, p53 induced apoptosis after gamma-irradiation was accompanied by a breakdown of the mitochondrial membrane potential (psi(m)) that was counteracted by growth stimulation. We propose that growth stimulation intercepted p53 proapoptotic signaling at the level of mitochondrial integrity, most likely by upregulating the antiapoptotic factors Bcl-x(L) and Bfl-1. Upregulation of Bcl-x(L) and of Bfl-1 upon growth stimulation was mediated by the PKC-dependent activation of NF-kappaB. Consequently, blocking PKC activity restored apoptosis in stimulated, irradiated splenocytes. The inherent coupling of growth stimulation with antiapoptotic signaling in primary lymphocytes might provide hints as to how precancerous lymphocytes bypass the need for mutational inactivation of p53. Thus, our findings might explain the relatively low frequency of p53 mutations in lymphomas in comparison to other tumor entities.
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PMID:Apoptosis or growth arrest: modulation of the cellular response to p53 by proliferative signals. 1255 69

To clarify the signaling pathways of oxidative stress-induced apoptosis in bovine aortic endothelial cells (BAEC), we treated cells with 1 mM H2O2 and investigated the roles of protein kinase C delta (PKC delta) and Ca2+ in the accumulation of p53 associated with apoptosis. The treatment of cells with H2O2 caused the accumulation of p53, which was inhibited by rottlerin (a PKC delta inhibitor) but not by BAPTA-AM (an intracellular Ca2+ chelator). PKC delta itself was activated through the phosphorylation at tyrosine residues. H2O2 induced the release of cytochrome c and the activation of caspases 3 and 9, and these apoptotic signals were inhibited by rottlerin and BAPTA-AM. These results suggest that PKC delta contributes to the accumulation of p53 and that Ca2+ plays a role in downstream signals of p53 leading to apoptosis in H2O2-treated BAEC.
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PMID:Roles of protein kinase C delta in the accumulation of P53 and the induction of apoptosis in H2O2-treated bovine endothelial cells. 1259 66

The tumor suppressor protein p53 is the most frequently mutated gene in human cancer. The function of p53 is not restricted to "guarding" against oncogenic stress, but also p53 can guard against the presence of DNA damage. One of the principal mechanisms by which cells achieve this is by regulating the p53 protein level although its phosphorylation and cellular localization also contribute to the regulation of its function. Since many tumors secrete growth factor(s) that inhibit apoptosis and support the growth of cancer cells, we investigated the effects of human epidermal growth factor (EGF) on human TNF-alpha-mediated induction of p53 and its transcriptional target, p21 in TNF-alpha sensitive human cervical carcinoma cell line, ME180S. We found that TNF-alpha can increase the cellular levels of p53, p21 and induce apoptosis in ME180S cells. However, pretreatment of cells with EGF can suppress all these effects of TNF-alpha. To determine which kinase(s) pathway was utilized by EGF to show these suppressive effects, cells were pretreated with inhibitors of MAPK, PI3K and PKC pathways. Among these only PKC inhibitor reversed all the suppressive effects of EGF. We also found that ME180S cells express only zeta, lambda, epsilon, iota, delta, theta, beta PKC subtypes and among these EGF treatment activate only PKC-delta redistribution to the membrane from the cytosol. An inhibitor of PKC, GF 109203X inhibited EGF-mediated suppression of TNF-alpha-induced accumulation of p53, p21 and induction of apoptosis. In summary, we concluded that EGF can protect ME180S cells from TNF-alpha-induced apoptosis through activation of PKC-delta.
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PMID:Suppression of TNF-alpha mediated apoptosis by EGF in TNF-alpha sensitive human cervical carcinoma cell line. 1279 34

Apoptosis and proliferation are intimately coupled. Some cell cycle regulators can influence both cell division and programmed cell death. The linkage of cell cycle and apoptosis has been recognized for c-Myc, p53, pRb, Ras, PKA, PKC, Bcl-2, NF-kappa B, CDK, cyclins and CKI. This review summarizes the different functions of the proteins presently known to control both apoptosis and cell cycle progression. These proteins can influence apoptosis or proliferation but different variables, including cell type, cellular environment and genetic background, make it difficult to predict the outcome of cell proliferation, cell cycle arrest or cell death. These important decisions of cell proliferation or cell death are likely to be controlled by more than one signal and are necessary to ensure a proper cellular response.
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PMID:Cell cycle and apoptosis. 1281 32

Previous reports have shown that, in certain cell types, p21(WAF-1), which plays a central role in cell proliferation, can be activated by HTLV-I Tax protein and by TPA. Tax and TPA are also known to stimulate HTLV-I gene expression. Since cell proliferation has a major impact on HTLV-I replication, it was of interest to investigate their effect on p21(WAF-1) in human T cells, which are the main target of HTLV-I in human infection. This study demonstrates that p21(WAF-1) is activated in such cells by both factors, each acting through a different mechanism that does not influence the other. The effect of TPA is shown to require PKC activity. Notably, however, examination of different PKC isoforms revealed that PKC-alpha and PKC-epsilon stimulated p21(WAF-1) expression, whereas PKC-eta was rather inhibitory and PKC-beta1 and beta2 were ineffective. All these isoforms were found to be activated by TPA in the employed T cells, but this apparent paradox was resolved by the observation that when coexpressed together in these cells, the stimulatory PKCs override the inhibitory isoform. Further experiments demonstrated that the PKC-induced p21(WAF-1) activation was mediated by binding of Sp1-p53 complex to the second most upstream of the six Sp1 recognition sites present in its promoter and that this effect did not require the cooperation of an p53-binding site.
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PMID:Role of protein kinase C and the Sp1-p53 complex in activation of p21(WAF-1) expression by 12-O-tetradecanoylphorbol-13-acetate in human T cells. 1291 33

p53 is one of the most important regulators of cell proliferation and differentiation and of programmed cell death, triggering growth arrest and/or apoptosis in response to different cellular stress signals. The sequence-specific DNA-binding function of p53 protein can be activated by several different stimuli that modulate the C-terminal domain of this protein. The predominant mechanism of activation of p53 sequence-specific DNA binding is phosphorylation at specific sites. For example, phosphorylation of p53 by PKC (protein kinase C) occurs in undamaged cells, resulting in masking of the epitope recognized by monoclonal antibody PAb421, and presumably promotes steady-state levels of p53 activity in cycling cells. In contrast, phosphorylation by cdk2 (cyclin-dependent kinase 2)/cyclin A and by the protein kinase CK2 are both enhanced in DNA-damaged cells. We determined whether one mechanism to account for this mutually exclusive phosphorylation may be that each phosphorylation event prevents modification by the other kinase. We used non-radioactive electrophoretic mobility shift assays to show that C-terminal phosphorylation of p53 protein by cdk2/cyclin A on Ser315 or by PKC on Ser378 can efficiently stimulate p53 binding to DNA in vitro, as well as binding of the monoclonal antibody Bp53-10, which recognizes residues 371-380 in the C-terminus of p53. Phosphorylation of p53 by CK2 on Ser392 induces its DNA-binding activity to a much lower extent than phosphorylation by cdk2/cyclin A or PKC. In addition, phosphorylation by CK2 strongly inhibits PKC-induced activation of p53 DNA binding, while the activation of p53 by cdk2/cyclin A is not affected by CK2. The presence of CK2-mediated phosphorylation promotes PKC binding to its docking site within the p53 oligomerization domain, but decreases phosphorylation by PKC, suggesting that competition between CK2 and PKC does not rely on the inhibition of PKC-p53 complex formation. These results indicate the crucial role of p53 C-terminal phosphorylation in the regulation of its DNA-binding activity, but also suggest that antagonistic relationships exist between different stress signalling pathways.
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PMID:Activation of the DNA-binding ability of latent p53 protein by protein kinase C is abolished by protein kinase CK2. 1464 Sep 83


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