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)

Ample data exist contending that wild-type p53 and E2F-1 cooperate to mediate apoptosis, that E2F-1-mediated apoptosis is p53 dependent in some situations, and that E2F-1 can induce accumulation of p53 in mammalian cells. These data support the investigation of the biological consequences of combined wild-typep53 and E2F-1 overexpression in human squamous cell carcinoma of the head and neck (SCCHN) for the purpose of developing apoptosis-inducing molecular intervention strategies for the management of this devastating disease. The recombinant adenovirus (Ad) vectors Ad-p53 and Ad-E2F-1 were used for wild-type p53 and E2F-1 gene transfers, respectively, into SCCHN cell lines TU138 and TU167. SCCHN cells transduced with either p53, E2F-1, or both underwent in vitro growth analysis, which revealed that simultaneous p53 and E2F-1 gene transfer did not result in enhanced growth inhibition. To explain our growth assay findings on the basis of potential negative molecular interactions between E2F-1 and p53, Western and Northern blotting analyses were performed to investigate the differential expression of the downstream p53-transactivated genes, p21Waf1 and BAX, under various p53 and E2F-1 gene transfer conditions. Whereas Western immunoblotting demonstrated that E2F-1 antagonized p53 induction of p21Waf1 and BAX, Northern blotting revealed that this interference was pretranslationally regulated and p53 dependent. Coimmunoprecipitation assay confirmed that the wild-type p53 and E2F-1 gene products formed protein-protein complexes in our cell lines. Our in vitro data demonstrated that in SCCHN, E2F-1 interferes with induction of p53-transactivated genes, probably through the formation of protein-protein complexes. Simultaneous p53 and E2F-1 gene transfer is not therapeutically advantageous in this in vitro model of SCCHN.
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PMID:Combination E2F-1 and p53 gene transfer does not enhance growth inhibition in human squamous cell carcinoma of the head and neck. 974 48

The mdm2 cellular protooncogene is involved in many human tumors where it has been shown to be overexpressed, including sarcomas, osteosarcomas, gliomas and others. The Mdm2 protein is believed to be oncogenic by binding and inactivating the p53 and Rb tumor suppressor gene products and by activating the E2F-1/DP-1 transcription factors, thus promoting the G1 to S phase transition. The mdm2 gene is activated transcriptionally by p53, thus forming an autoregulatory negative feedback loop. This feedback loop is important in normal cells and when cells are exposed to various genotoxic agents. By activating its own negative regulator, p53 would signal the cells to resume proliferation after a p53-mediated G1 arrest in response to DNA damage. The review aims to detail the functions of Mdm2 in normal and tumor cells. We also discuss several recent data suggesting that Mdm2 may exhibit activities unrelated to its well known function as a negative regulator of p53 activities.
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PMID:[Mdm2, p53 and the cell cycle: when well enough is best left alone]. 976 46

Interleukin-1alpha (IL-1alpha) is a multifunctional cytokine that promotes inflammation, tissue remodeling and epithelial hyperplasia. Keratinocytes produce and sequester large amounts of biologically active IL-1alpha which can be released after injury or infection. We show that high level expression of human papillomavirus (HPV) type 16 E6 and E7 oncoproteins enhanced release of IL-1alpha from cultures of normal cervical keratinocytes (relative effectiveness E7 > E6/E7 >> E6 > control). The amount of IL-1alpha released was directly related to the ability of E7 or E6/E7 to stimulate apoptosis. E7 proteins that bound the retinoblastoma protein (Rb) strongly (HPV-16 and -18) induced more IL-1alpha release than those that bound poorly (HPV-6 and an HPV-16 E7 24gly mutant). Furthermore, overexpression of the E2F-1 transcription factor, a downstream target of Rb, induced extensive apoptosis and IL-1alpha release. Apoptosis and IL-1alpha release in response to growth factor removal occurred in part through a p53-independent pathway as coexpression of E6 and downregulation of p53 did not prevent either response. Immunohistochemical analyses showed that IL-1alpha was expressed by keratinocytes in normal cervical epithelia, low and high grade dysplasias, and cervical carcinomas. However, HPV-16 E6/E7 RNA expression and apoptosis increased in parallel in proliferating keratinocytes in severe dysplasias and carcinomas suggesting that IL-1alpha release is associated with progression to high grade disease. Thus, high level expression of the HPV-16 E7 protein sensitizes keratinocytes to apoptosis which results in release of IL-1alpha.
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PMID:Human papillomavirus type 16 E7 protein sensitizes cervical keratinocytes to apoptosis and release of interleukin-1alpha. 977 62

Mice mutant for the Rb tumor suppressor gene die in mid-gestation with defects in erythropoiesis, cell cycle control, and apoptosis. We show here that embryos mutant for both Rb and its downstream target E2f-1 demonstrate significant suppression of apoptosis and S phase entry in certain tissues compared to Rb mutants, implicating E2f-1 as a critical mediator of these effects. Up-regulation of the p53 pathway, required for cell death in these cells in Rb mutants, is also suppressed in the Rb/E2f-1 double mutants. However, double mutants have defects in cell cycle regulation and apoptosis in some tissues and die at approximately E17.0 with anemia and defective skeletal muscle and lung development, demonstrating that E2F-1 regulation is not the sole function of pRB in development.
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PMID:Mutation of E2f-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos. 977 68

The transcription factor E2F-1 drives cell cycle progression at the G1- to S-phase boundary; however, overexpression of E2F-1 can induce apoptosis. We show here that E2F-1 protein levels increase in human medulloblastoma, glioma, lung, colon, and bladder cancer cell lines (n=7) following treatment with the DNA damaging agents adriamycin or etoposide. This induction of E2F-1 occurs independently of Rb or p53 status and involves new protein synthesis. Although E2F-1 protein levels increase following DNA damage, several genes transcriptionally targeted by E2F-1 are not similarly induced. Rather, induction of E2F-1 in the tumor cells correlates with their sensitivity to adriamycin or to etoposide. Correspondingly, fibroblasts from E2F-1 knockout mice are more resistant to DNA damage than cells from normal mice. Overexpression of E2F-1 protein in tumor cell lines infected with an adenovirus encoding wild-type E2F-1 leads to enhanced cytotoxicity following exposure to DNA damaging agents, which results from enhanced apoptosis. The results of this study implicate a role for E2F-1 in p53-independent cytotoxicity of chemotherapy and provide a pharmacological tool for increasing levels of the apoptosis-inducing E2F-1 protein.
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PMID:p53-independent increase in E2F-1 expression enhances the cytotoxic effects of etoposide and of adriamycin. 986 3

Current therapy for glioma is suboptimal. The transfer of apoptosis genes to tumors constitutes one of the most promising strategies for cancer gene therapy. We have previously shown that massive apoptosis occurs when wild-type p53 or E2F-1 expression is induced in glioma. However, the mechanism of action and the efficiency in inducing apoptosis of these two proteins are not similar. Adenovirus-mediated p53 gene transfer is ineffective in causing apoptosis in glioma cells that retain wild-type p53 genotype or overexpress the p21 protein. The p16/Rb/E2F pathway is the most frequent target of genetic alterations in gliomas, and therefore constitutes a suitable target for gene therapy strategies. However, the transfer of either the p16 or Rb gene to glioma cells results in cytostatic effect. The E2F-1 protein is able to induce generalized apoptosis in gliomas independently of the p53, p16 or Rb status. In addition, p21- or p16-mediated growth arrest did not protect glioma cells from E2F-1-mediated apoptosis. The apoptotic molecule bax is induced in p53-mediated apoptosis, but bax is not induced in E2F-1-mediated apoptosis in glioma cells. Careful selection of patients may be necessary before designing therapeutic strategies using either p53 or E2F-1 as a therapeutic tools for glioma patients.
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PMID:Gene therapy for gliomas: p53 and E2F-1 proteins and the target of apoptosis. 986 90

AT cells exhibit defective cell cycle regulation following DNA damage. Previous studies have shown that induction of p53 and p21 proteins are delayed in response to ionizing radiation, resulting in the failure of G1/S checkpoint in AT cells. In this study, further investigation of the molecular mechanisms underlying G1/S phase progression in AT cells was conducted. Exponentially growing normal and AT cells were exposed to 2 Gy of ionizing radiation and the expression levels and functional activities of Rb and E2F-1 proteins were determined. We observed overexpression of hyperphosphorylated Rb and E2F-1 proteins in AT cells, which was unaffected post-irradiation. Furthermore, gel shift assays showed that E2F-1-DNA binding was constitutive in AT cells, whereas it was inhibited in control cells following exposure to ionizing radiation. The data suggests that abnormalities in the function of Rb and E2F-1 proteins may also be responsible for the failure of AT cells to arrest in the G1/S checkpoint in response to DNA damage.
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PMID:Overexpression of Rb and E2F-1 in ataxia-telangiectasia lymphocytes. 986 30

Tomudex (ZD1694) is a specific antifolate-based thymidylate synthase inhibitor active in a variety of solid tumor malignancies. Studies were carried out in vitro to evaluate downstream molecular alterations induced as a consequence of the potent and sustained inhibition of thymidylate synthase by Tomudex. Twenty-four hours following the initial 2-h treatment with Tomudex, human A253 head and neck squamous carcinoma cells, not expressing p53 and p21(WAF1), were accumulated with DNA content characteristic of early S phase of the cell cycle with a concomitant reduction of cells in G1 and G2/M phases. The changes in cyclin and cdk protein expression and their kinase activities were examined in control and drug-treated A253 cells. Tomudex treatment resulted in the decrease in p27(kip1) expression, with an increase in cyclin E and cdk2 protein expression and kinase activities 24 h after a 2-h exposure. Although cyclin A protein expression was markedly increased, cyclin A kinase activity was only slightly increased. Cyclin D1, cyclin B, cdk4, and cdc2 protein expression and kinase activities remain constant. Lack of activation of cyclin A- and B-cdc2 was associated with a reduced proportion of cells in G2/M phases. Increased cyclin E-cdk2 protein expression was accompanied by the inhibition of DNA synthesis, with a decrease in E2F-1 expression. These results propose that cyclin E-cdk2 kinase can negatively regulate DNA replication. The studies with dThyd rescue from cyclin E-cdk2 protein overexpression and growth inhibition by Tomudex indicate that increased cyclin E-cdk2 protein expression is associated with effective inhibition of thymidylate synthase and resultant dNTP pool imbalance. Provision of dThyd more than 24 h after exposure to Tomudex allowed cells to replicate DNA for a single cycle back to G1, but did not prevent the profound growth-inhibitory effect manifested in the following 5 days. Tomudex treatment resulted in a time-dependent induction of the megabase DNA fragments, followed by secondary 50- to 300-kb DNA fragmentation. The 50- to 300-kb DNA fragmentation may be derived from the inhibition of DNA synthesis associated with cyclin E-cdk2 activation. These results suggest that the megabase DNA fragmentation is induced as a consequence of inhibition of thymidylate synthase by Tomudex and kilobase DNA fragmentation may correlate with the reduction of p27(kip1) expression and the increase in cyclin E and cdk2 kinase activities. Activation of cyclin E and cdk2 kinases allows cells to transit from G1 to S phase accompanied by the inhibition of DNA synthesis. The changes in cell cycle regulatory proteins associated with growth inhibition and DNA damage by Tomudex are not p53 dependent.
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PMID:Cyclin E-cdk2 activation is associated with cell cycle arrest and inhibition of DNA replication induced by the thymidylate synthase inhibitor Tomudex. 1004 61

The loss of p53-mediated apoptosis (programmed cell death) has been implicated as an important event in tumour progression in a number of systems. p53 can induce or potentiate apoptosis through several mechanisms, both by regulating the expression of genes which can participate in the apoptotic response and through transcriptionally independent means. There appears to be cell type variability in both the response to p53 expression and in the requirement for p53 transcriptional transactivation for the induction of apoptosis. It seems clear, however, that the induction of p53 in untransformed cells is more likely to result in cell-cycle arrest, whereas the expression of p53 in their transformed counterparts is more likely to result in the induction of apoptosis, and this may, in part, reflect the deregulated expression of E2F-1 in tumour cells. The synergistic action of p53 and E2F-1 in the induction of apoptosis has raised the possibility that the reactivation of p53 in transformed cells can be an effective tumour therapy.
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PMID:Mechanisms of p53-mediated apoptosis. 1006 49

Expression of the DMP1 transcription factor, a cyclin D-binding Myb-like protein, induces growth arrest in mouse embryo fibroblast strains but is devoid of antiproliferative activity in primary diploid fibroblasts that lack the ARF tumor suppressor gene. DMP1 binds to a single canonical recognition site in the ARF promoter to activate gene expression, and in turn, p19(ARF) synthesis causes p53-dependent cell cycle arrest. Unlike genes such as Myc, adenovirus E1A, and E2F-1, which, when overexpressed, activate the ARF-p53 pathway and trigger apoptosis, DMP1, like ARF itself, does not induce programmed cell death. Therefore, apart from its recently recognized role in protecting cells from potentially oncogenic signals, ARF can be induced in response to antiproliferative stimuli that do not obligatorily lead to apoptosis.
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PMID:Induction of ARF tumor suppressor gene expression and cell cycle arrest by transcription factor DMP1. 1009 51


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