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)

Cyclin G2, together with cyclin G1 and cyclin I, defines a novel cyclin family expressed in terminally differentiated tissues including brain and muscle. Cyclin G2 expression is up-regulated as cells undergo cell cycle arrest or apoptosis in response to inhibitory stimuli independent of p53 (Horne, M., Donaldson, K., Goolsby, G., Tran, D., Mulheisen, M., Hell, J. and Wahl, A. (1997) J. Biol. Chem. 272, 12650-12661). We tested the hypothesis that cyclin G2 may be a negative regulator of cell cycle progression and found that ectopic expression of cyclin G2 induces the formation of aberrant nuclei and cell cycle arrest in HEK293 and Chinese hamster ovary cells. Cyclin G2 is primarily partitioned to a detergent-resistant compartment, suggesting an association with cytoskeletal elements. We determined that cyclin G2 and its homolog cyclin G1 directly interact with the catalytic subunit of protein phosphatase 2A (PP2A). An okadaic acid-sensitive (<2 nm) phosphatase activity coprecipitates with endogenous and ectopic cyclin G2. We found that cyclin G2 also associates with various PP2A B' regulatory subunits, as previously shown for cyclin G1. The PP2A/A subunit is not detectable in cyclin G2-PP2A-B'-C complexes. Notably, cyclin G2 colocalizes with both PP2A/C and B' subunits in detergent-resistant cellular compartments, suggesting that these complexes form in living cells. The ability of cyclin G2 to inhibit cell cycle progression correlates with its ability to bind PP2A/B' and C subunits. Together, our findings suggest that cyclin G2-PP2A complexes inhibit cell cycle progression.
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PMID:Cyclin G2 associates with protein phosphatase 2A catalytic and regulatory B' subunits in active complexes and induces nuclear aberrations and a G1/S phase cell cycle arrest. 1195 89

Oncoprotein Myc, hetero-dimerized with Max through a b/HLH/Zip region, is a transcription factor that governs important cellular processes such as cell cycle entry, proliferation and differentiation. We found that linoleic acid, isolated from Pollen Typhae, and other unsaturated fatty acids have strong inhibitory effects on the binding of Myc-Max heterodimer to an E-box DNA site (CA(C/T)GTG). The interaction of a fatty acid with a protein dimer, not with DNA, is assumed to block the entire Myc-Max-DNA complex formation. Unsaturated fatty acids also showed cytotoxicity against a SNU16 human stomach cancer cell line and conjugated linoleic acid suppressed mRNA expression of several myc-target genes; ornithine decarboxylase, p53, cdc25a in the SNU16 cells.
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PMID:Unsaturated fatty acids bind Myc-Max transcription factor and inhibit Myc-Max-DNA complex formation. 1240 60

Freeze-dried black raspberries have been shown to inhibit the development of chemically induced esophageal and colon cancer in rodents. In addition, organic extracts of black raspberries inhibit benzo(a)pyrene (BaP)-induced cell transformation in vitro. The molecular mechanisms through which black raspberries inhibit carcinogenesis remain unclear. We investigated the effects of black raspberry extracts on transactivation of activated protein 1 (AP-1) and nuclear factor kappaB (NFkappaB) induced by BaP diol-epoxide (BPDE), the ultimate carcinogen of BaP, in mouse epidermal JB6 Cl 41 (Cl 41) cells. Black raspberries were extracted with methanol, and the methanol extract was partitioned and chromatographed into several fractions designated RU-F003, RU-F004, RU-DM, and RU-ME. Pretreatment of Cl 41 cells with RU-F003, RU-DM, or RU-ME resulted in an inhibition of BPDE-induced AP-1 and NFkappaB activities. The RU-ME fraction was the most potent inhibitor among the fractions tested. In contrast, fraction RU-F004 did not inhibit BPDE-induced AP-1 or NFkappaB activities in Cl 41 cells. The inhibitory effects of RU-ME on BPDE-induced activation of AP-1 and NFkappaB appear to be mediated via inhibition of mitogen activated protein kinase activation and inhibitory subunit kappaB phosphorylation, respectively. Pretreatment of cells with berry fractions did not result in an inhibition of BPDE binding to DNA; thus, this was not a mechanism of reduced AP-1 and NFkappaB activities. None of the fractions was found to affect p53-dependent transcription activity. In view of the important roles of AP-1 and NFkappaB in tumor promotion/progression, these results suggest that the ability of black raspberries to inhibit tumor development may be mediated by impairing signal transduction pathways leading to activation of AP-1 and NFkappaB. The RU-ME fraction appears to be the major fraction responsible for the inhibitory activity of black raspberries.
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PMID:Inhibition of benzo(a)pyrene diol-epoxide-induced transactivation of activated protein 1 and nuclear factor kappaB by black raspberry extracts. 1246 Aug 99

We have used microarray technology to identify the transcriptional targets of Rho subfamily guanosine 5'-triphosphate (GTP)ases in NIH3T3 cells. This analysis indicated that murine fibroblasts transformed by these proteins show similar transcriptomal profiles. Functional annotation of the regulated genes indicate that Rho subfamily GTPases target a wide spectrum of functions, although loci encoding proteins linked to proliferation and DNA synthesis/transcription are upregulated preferentially. Rho proteins promote four main networks of interacting proteins nucleated around E2F, c-Jun, c-Myc and p53. Of those, E2F, c-Jun and c-Myc are essential for the maintenance of cell transformation. Inhibition of Rock, one of the main Rho GTPase targets, leads to small changes in the transcriptome of Rho-transformed cells. Rock inhibition decreases c-myc gene expression without affecting the E2F and c-Jun pathways. Loss-of-function studies demonstrate that c-Myc is important for the blockage of cell-contact inhibition rather than for promoting the proliferation of Rho-transformed cells. However, c-Myc overexpression does not bypass the inhibition of cell transformation induced by Rock blockage, indicating that c-Myc is essential, but not sufficient, for Rock-dependent transformation. These results reveal the complexity of the genetic program orchestrated by the Rho subfamily and pinpoint protein networks that mediate different aspects of the malignant phenotype of Rho-transformed cells.
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PMID:Transcriptomal profiling of the cellular transformation induced by Rho subfamily GTPases. 1721 2

A novel class of platinum(II) complexes of pyridine sulfide derivatives of triazine was synthesized, characterized, and investigated using the human breast cancer cell line, MDA-MB-468. S-30 was one of the most potent derivatives of its class (IC(50), 0.39 microM) eliciting the greatest biological response. S-30 induced arrest in the G1 phase and apoptosis (TUNEL assay) in a p53/p21(WAF1/CIP1)-consistent manner. Modeling and docking experiments were performed for three known targets for cisplatin, d(GpG), d(ApG), and a protein (Cu/Zn superoxide dismutase, SOD) from bovine origin. A Blast search of bovine SOD was performed to identify analogous human protein targets resulting in about 22 human proteins. A multi-sequence alignment of those targets showed >80% sequence identity and >88% similarity. One of them is SOD1 that is differentially expressed (based on global gene expression pattern) in various forms of cancer and other diseases. SOD1 controls apoptosis via p53/BAD/BAX/BCL2 in the amyotrophic lateral sclerosis (ALS) pathway and is also involved in various other KEGG's pathways. Results suggest that the S-30 is a potential cytotoxic agent.
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PMID:A new platinum complex of triazine demonstrates G1 arrest with novel biological profile in human breast cancer cell line, MDA-MB-468. 1732 43

Chromosomal aberrations are important prognostic parameters in acute myeloid leukemia (AML). Indicators of poor prognosis include del(5q)/-5, del(7q)/-7, abnormal 3q or complex karyotype. In recent years, it has become clear that aberrations in 17p represent one of the indicators of poor prognosis in haematological malignancies. In AML, deletions in 17p have been shown to indicate a dismal prognosis; genetic aberrations in 9p have also been discussed as influencing long-term survival in AML. In this study, we correlated genetic abnormalities in chromosomes 9 and 17 in patients with de novo AML to in vitro cytotoxicity of conventional anti-leukemic drugs, and long-term overall survival. Blast cells were isolated from 387 patients diagnosed with AML. Chromosomal analysis was successful in 336 cases. All samples were tested for in vitro cytotoxicity against fludarabine, amsacrine, mitoxantrone, etoposide, daunorubicin and Ara-C after being cultured for 4 days, using an ATP assay. Among the 336 patients, five main groups were identified. Abnormal chromosome 17 (n = 22), abnormal 9p (n = 13), monosomy 7 or deletion 7q (n = 35), complex karyotype (n = 52) and normal karyotype (n = 132). Patients with abnormalities of chromosome 17 showed significantly greater resistance to all drugs tested and significantly shorter overall survival compared with patients with normal and complex karyotypes (p = 0.0001 and 0.041, respectively). All patients with abnormalities of chromosome 17 died within 11 months of diagnosis. A tendency towards shorter overall survival and greater drug resistance was also noted when comparing chromosome 17 abnormalities with del(7q)/-7, but the differences did not reach statistical significance. Patients with abnormal 9p showed significantly shorter overall survival but did not differ significantly as regards in vitro drug resistance compared with patients presenting with a normal karyotype. Chromosomal abnormalities affecting the p53 pathway have a significant impact on cytostatic drug resistance and survival in AML. Developing new drugs targeting the p53 pathway could be a way to improve treatment of AML.
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PMID:Chromosomal aberrations in 17p predict in vitro drug resistance and short overall survival in acute myeloid leukemia. 1829 13

Early metastasis and a poor five-year survival make lung cancer the leading cause of cancer related deaths worldwide. The clinical profile of lung cancer patients in India differs from the West as they present earlier, with squamous cell carcinoma being the commonest histological type. We compared gene expression profiles in primary lung squamous cell carcinoma (LSCC) and matched normal lung tissues in Asian Indians. Using suppression subtractive hybridization, two subtracted cDNA libraries containing differentially expressed genes in the tumors were constructed. Differential expression was confirmed by reverse Northern blot analysis. DNA of confirmed clones was sequenced and subjected to GenBank Blast searches. RNA expression levels were then analyzed by Northern blotting and validated by semiquantitative RT-PCR (in 10 cases of NSCLC). Seventeen differentially expressed gene cDNA fragments of LSCC were analyzed. The differentially expressed genes included those associated with cellular metabolism, cell-cycle, -structure, -adhesion, transcription, proliferation, apoptosis and signal transduction. The study provided first evidence that KIAA0767, a Death Inducing Protein, a novel p53 independent target of E2F1, and Geminin, an inhibitor of DNA replication are differentially expressed in LSCC. Identification of the differentially expressed genes in lung cancer in this study may serve as better molecular markers for early diagnosis and identifying novel intervention sites for anticancer therapy.
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PMID:Molecular profiling of genes in squamous cell lung carcinoma in Asian Indians. 1830 64

Cryolesion of the frontoparietal cortex in mice is a well-described brain injury paradigm that results in increased astrogliosis surrounding the lesion site and is accompanied by a prominent increase in the MAO-B levels in astrocytes. Whether these increased MAO-B levels contribute to cellular damage or modulate reactive astrocytosis remains unclear. MAO-B activity may contribute to cellular damage, since its metabolism products are highly toxic to the cells. Additionally, it has been suggested that MAO-B inhibition may regulate astrocytic reaction. In this study, we have determined the relative contribution of MAO-B activity to the outcome following freeze injury. Freeze injury induced a prominent increase of several inflammatory markers, including ICAM, Mac-1, EB22, and GFAP. Inhibition of MAO-B activity using the selective inhibitor PF9601N did not reduce this cryolesion-induced inflammatory response. Additional data revealed that the expression of several cryolesion-induced cell death genes, such as Fas, Rip, p53, and ICE, was not reduced in PF9601N-treated mice, evidencing that MAO-B activity did not contribute to cryolesion-induced cell death. Definitive functional analysis of the mice using the ladder beam task revealed that MAO-B inhibition did not improve the cryolesion-induced motor impairment. These data strongly suggest that, although MAO-B is highly expressed in the area surrounding the lesion site, its activity does not contribute to the cellular damage or play any role in regulating astrocytic reactivity.
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PMID:Monoamine oxidase-B activity is not involved in the neuroinflammatory response elicited by a focal freeze brain injury. 1883 Oct 59

Hypericum perforatum (St. John's wort) is well-established for its antidepressant activity throughout the world and also various other species within this genus are used in different folk medicines. Hyperforin of St. John's wort inhibited growth of cancer cell lines and the use of hypericin (another compound of H. perforatum) in cancer photodynamic therapy is proposed. Therefore, we investigated the anti-cancer properties of H. adenotrichum Spach (Guttiferae), an endemic species in Turkey called 'kantaron', which is used for wound healing and antiseptic effects. Freeze-dried plant was extracted with petroleum ether, dichloromethane, ethyl acetate, and methanol and the bioactivity of these extracts was analysed by proliferation assay, cell death determination, by investigating protein expression profiles specific for cell cycle arrest and apoptosis as well as composition by HPLC. The strongest anti-proliferative activity was determined for the petroleum ether extract with an IpC50 of approximately 5.8 microg/ml medium (referring to 1 mg dried plant) which correlated with cyclin D1 suppression and p21 induction. This extract also induced phosphorylation of H2AX, and activated caspase-3 followed by signature-type cleavage of PARP resulting in approximately 50% apoptosis at 23.2 microg/ml after 24 h of treatment. Neither hyperforin, hypericin, or amentoflavone contributed to these properties. To the best of our knowledge, we report for the first time that the endemic plant H. adenotrichum Spach exhibits potent p53-independent anti-neoplastic properties due to yet unexplored Hypericum constituents.
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PMID:In vitro anti-neoplastic activity of the ethno-pharmaceutical plant Hypericum adenotrichum Spach endemic to Western Turkey. 1972 64

Lime (Citrus aurantifolia Swingle) is one of the major citrus fruits and widely consumed, but there is limited evidence about its health-promoting properties. Hence, an investigation was conducted to understand the chemopreventive effects of lime juice on pancreatic cancer cells and the possible mechanism for induction of apoptosis using Panc-28 cells. Freeze-dried lime juice was extracted with different solvents, such as chloroform, acetone, MeOH, and MeOH/water (8:2). The chloroform extract showed the highest (85.4 and 90%) radical-scavenging activity by 1,1-diphenyl-2-picryl hydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) methods at 624 microg/mL, whereas the MeOH/water extract showed the lowest (<20%) activity. The active components were identified by high-performance liquid chromatography (HPLC) using a C-18 column as rutin, neohesperidin, hesperidin, and hesperitin. Furthermore, the limonoids identified are limonexic acid, isolimonexic acid, and limonin. All of the extracts of lime juice inhibited Panc-28 cancer cell growth. The MeOH extract exhibited the maximum activity, with an IC50 value of 81.20 microg/mL after 72 h. The inhibition of Panc-28 cells was in the range of 73-89%, at 100 microg/mL at 96 h. The involvement of apoptosis in induction of cytotoxicity was confirmed by expression of Bax, Bcl-2, casapase-3, and p53. The results of the present study clearly indicate that antioxidant activity is proportionate to the content of flavonoids and proliferation inhibition ability is proportionate to the content of both flavonoids and limonoids.
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PMID:Bioactive compounds from Mexican lime ( Citrus aurantifolia ) juice induce apoptosis in human pancreatic cells. 1991 25


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