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)

The p53 tumor suppressor protein is a key regulator of cell cycle and death that is involved in many cell signaling pathways and is tightly regulated in mammalian cells. Post-translational modifications of p53 have been investigated previously mainly using antibodies. In this study, utilizing LC-MS/MS analysis, we have characterized p53 protein from COS-1 cells. Several already known post-translational modifications were observed, such as phosphorylation on serines 15, 33, 315, and 392 as well as acetylation on lysines 305, 370, 372, 373, 381, 382, and 386. Interestingly novel acetylation sites were identified at lysines 319 and 357. This study confirmed that p53 is a highly acetylated protein and revealed new acetylation sites that might aid the further understanding of p53 regulation.
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PMID:Identification of new p53 acetylation sites in COS-1 cells. 1915 8

Transcription factors P53 and FOXO are both activated in response to stresses via protein-protein interactions, leading to events such as cell survival or apoptosis. To clarify the mechanisms that regulate FOXO activity, we analyzed the intermolecular interaction of FOXO3a and P53. FOXO3a and P53 interacted in COS-7 cells, and transcriptional activity of FOXO3a was suppressed by P53, but P53 was not affected by FOXO3a. RT-PCR revealed that expression of the endogenous apoptosis-inducible genes Bim and Bcl6 was decreased markedly by co-expression of P53 with them, but expression of p27 and CyclinG2 was not. In addition, treatment with 500 microM H2O2 for 30 min to 1h to mimic oxidative stress promoted protein binding. Serum deprivation and drug treatment also affected the binding of FOXO3a and P53. These findings suggest that FOXO3a controls cellular function by changing its molecular interaction with P53 to mediate transcription factor activity under stress stimuli.
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PMID:P53 negatively regulates the transcriptional activity of FOXO3a under oxidative stress. 1942 86

Expression and activity of the germinal center kinase [corrected] SLK are increased during kidney development and recovery from renal ischemia-reperfusion injury. SLK promotes apoptosis, in part, via pathway(s) involving apoptosis signal-regulating kinase-1 and p38 mitogen-activated protein kinase. This study addresses the role of p53 as a potential effector of SLK. p53 transactivation was measured after transient transfection of a luciferase reporter plasmid that contains a p53 cis-acting enhancer element. Overexpression of SLK in COS-1 cells and cotransfection of SLK and p53-wild type (wt) cDNAs in glomerular epithelial cells (GECs) stimulated p53 transactivational activity, as measured by a p53 response element-driven luciferase reporter. In GECs, chemical anoxia followed by glucose reexposure (in vitro ischemia-reperfusion) increased p53 reporter activity, and this increase was amplified by overexpression of SLK. Expression of SLK induced p53 phosphorylation on serine (S)-33 and S315. In GECs, cotransfection of SLK with p53-wt, p53-S33A, p53-S315A, or p53-S33A+S315A mutants showed that only the double mutation abolished the SLK-induced increase in p53 reporter activity. SLK-induced stimulation of p53 reporter activity was attenuated by inhibition of JNK. Overexpression of SLK amplified apoptosis induced by subjecting cells to in vitro ischemia-reperfusion injury, while ectopic expression of a dominant negative SLK mutant attenuated the ischemia-reperfusion-induced apoptosis. The p53 transactivation inhibitor pifithrin-alpha significantly attenuated the amount of apoptosis after ischemia-reperfusion and SLK overexpression. Thus SLK induces p53 phosphorylation and transactivation, which enhances apoptosis after in vitro ischemia-reperfusion injury.
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PMID:The Ste20-like kinase SLK promotes p53 transactivation and apoptosis. 1964 Aug 99

Drug resistance in cancer cells involves complex molecular mechanisms and ovarian carcinoma cells become resistant to chlorambucil (Cbl) after continuous treatment. This drug- and ionizing radiation-resistant cells have lower level of endogenous ROS (reactive oxygen species) compared with sensitive cells. Elevation of the cellular ROS level by exogenous ROS generation increases the sensitivity of Cbl to resistant cells. In contrast, antioxidants prevent the sensitization of resistant cells to Cbl by H(2)O(2), COS (chronic oxidative stress) or NOO(-). The molecular mechanism of drug sensitivity with COS has been investigated by microarray gene expressions followed by gene network analysis and it reveals that a cdc42/rac1 guanine exchange factor, ARHGEF6, with p53 and DNA-Pkc (PRKDC) is central to induce apoptosis in Cbl(cos) (Cbl with COS) cells. mRNA and protein levels of major gene network pathway differ significantly in Cbl(cos) cells than in Cbl-treated cells. Moreover, DNA-PKc physically interacts with ARHGEF6 and p53 mostly in the nucleus of Cbl-treated cells, whereas in Cbl(cos)-treated cells, its interactions are mostly in the cytoplasm. These results suggest that low doses of Cbl and very low doses of COS together kill Cbl-resistant ovarian carcinoma cells and ARHGEF6 signaling may have an instrumental role in induction of apoptosis in Cbl(cos) cells.
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PMID:Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells. 1991 61

Previous research has shown that muscarinic receptors (MAChRs) show loss of sensitivity in aging and AD and are selectively sensitive to oxidative stress (OS). Thus, COS-7 cells transfected (tn) with MAChR subtype M1 show > OS sensitivity [as reflected in the ability of the cell to extrude or sequester Ca(2+) following depolarization (recovery) by oxotremorine (oxo) and exposure to dopamine (DA) or amyloid beta (Abeta)] than M3-transfected COS-7 cells. Blueberry (BB) extract pretreatment prevented these deficits. Research has also indicated that C2 ceramide (Cer) has several age-related negative cellular effects (e.g., OS). When these cells were treated with Cer, the significant decrements in the ability of both types of tn cells to initially respond to oxo were antagonized by BB treatment. Present experiments assessed signaling mechanisms involved in BB protection in the presence or absence of DA, Abeta, and/or Cer in this model. Thus, control or BB-treated M1 and M3 tn COS-7 cells were exposed to DA or Abeta(42) in the presence or absence of Cer. Primarily, results showed that the effects of DA or Abeta(42) were to increase stress (e.g., PKCgamma, p38MAPK) and protective signals (e.g., pMAPK). Cer also appeared to raise several of the stress and protective signals in the absence of the other stressors, including PKCgamma, pJNK, pNfkappaB, p53, and p38MAPK, while not significantly altering MAPK, or Akt. pArc was, however, increased by Cer in both types of transfected cells. The protective effects of BB when combined with Cer generally showed greater protection when BB extract was applied prior to Cer, except for one protective signal (pArc) where a greater effect was seen in the M3 cells exposed to Abeta(42.) In the absence of the Abeta(42) or DA, for several of the stress signals (e.g., pNfkappaB, p53), BB lowered their Cer-induced increases in M1- and M3-transfected cells. We are exploring these interactions further, but it is clear that increases in ceramide, to the same levels as are seen in aging, can have profound effects on calcium clearance and signaling during oxidative stress.
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PMID:Blueberry treatment antagonizes C-2 ceramide-induced stress signaling in muscarinic receptor-transfected COS-7 cells. 2017 93

LBH is a transcription factor as a candidate gene for CHD associated with partial trisomy 2p syndrome. To identify potential LBH-interacting partners, a yeast two-hybrid screen using LBH as a bait was performed with a human heart cDNA library. One of the clones identified encodes alphaB-crystallin. Co-immunoprecipitation and GST pull-down assays showed that LBH interacts with alphaB-crystallin, which is further confirmed by mammalian two-hybrid assays. Co-localization analysis showed that in COS-7 cells, alphaB-crystallin that is cytoplasmic alone, accumulates partialy in the nucleus when co-transfected with LBH. Transient transfection assays indicated that overexpression of LBH or alphaB-crystallin reduced the transcriptional activities of p53 and p21, respectively, Overexpression of both alphaB-crystallin and LBH together resulted in a stronger repression of the transcriptional activities of p21 and p53. These results showed that the interaction of LBH and alphaB-crystallin may inhibit synergistically the transcriptional regulation of p53 and p21.
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PMID:Synergistic efficacy of LBH and alphaB-crystallin through inhibiting transcriptional activities of p53 and p21. 2058 34

Infection of mycoplasmas has been linked to various human diseases including arthritis, pneumonia, infertility and cancer. While Mycoplasma hyorhinis and Mycoplasma fermentans have been detected in gastric adenocarcinomas, the mechanisms underlyine the pathogenesis are unknown. In this study, cell growth kinetics, Hoechst 33258 staining, DNA ladder assays, Western blotting analysis and cDNA microarray assays were performed to investigate the roles of M. hyorhinis and M. fermentans during infection of mammalian cells. Our data demonstrated that these mycoplasmas inhibid the growth of immortalised cell lines (32D and COS-7) ane tumor cell lines (HeLa and AGS). In addition, the infection of the 32D cell line with M. hyorhinis and M. fermentans induced compression of the nucleus, degradation of the cell genome and dysregulation of the expression of genes related to proliferation, apoptosis, tumorigenesis, signaling pathway and metabolism. Apoptosis related proteins Bcl-2, Bid and p53 were down-regulated, Fas was up-regulated and Bax was dysregulated in mycoplasma-infected 32D cells. Together, our data demonstrated that infection of mycoplasmas inhibitd cele growts through modification of gene expression profiles and post-translation modification of proliferation and apoptosis related proteins.
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PMID:Mycoplasma hyorhinis and Mycoplasma fermentans induce cell apoptosis and changes in gene expression profiles of 32D cells. 2244 3

The p53 tumor suppressor protein accumulates to very high concentrations in normal human fibroblasts infected by adenovirus type 5 mutants that cannot direct assembly of the viral E1B 55-kDa protein-containing E3 ubiquitin ligase that targets p53 for degradation. Despite high concentrations of nuclear p53, the p53 transcriptional program is not induced in these infected cells. We exploited this system to examine select post-translational modifications (PTMs) present on a transcriptionally inert population of endogenous human p53, as well as on p53 activated in response to etoposide treatment of normal human fibroblasts. These forms of p53 were purified from whole cell lysates by means of immunoaffinity chromatography and SDS-PAGE, and peptides derived from them were subjected to nano-ultra-high-performance LC-MS and MS/MS analyses on a high-resolution accurate-mass MS platform (data available via ProteomeXchange, PXD000464). We identified an unexpectedly large number of PTMs, comprising phosphorylation of Ser and Thr residues, methylation of Arg residues, and acetylation, ubiquitinylation, and methylation of Lys residues-for example, some 150 previously undescribed modifications of p53 isolated from infected cells. These modifications were distributed across all functional domains of both forms of the endogenous human p53 protein, as well as those of an orthologous population of p53 isolated from COS-1 cells. Despite the differences in activity, including greater in vitro sequence-specific DNA binding activity exhibited by p53 isolated from etoposide-treated cells, few differences were observed in the location, nature, or relative frequencies of PTMs on the two populations of human p53. Indeed, the wealth of PTMs that we have identified is consistent with a far greater degree of complex, combinatorial regulation of p53 by PTM than previously anticipated.
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PMID:Extensive post-translational modification of active and inactivated forms of endogenous p53. 2405 36

During recent years, significant development has been achieved in carbon nanotube conjugated with polymer system for drug delivery system (DDS). In the present study, we have prepared functionalized single walled carbon nanotube conjugated with chitooligosaccharide (f-SWNT-COS) as a Drug Delivery System. In addition, drug Gliotoxin (GTX) and targeting molecules (Lysozyme, p53 and Folic acid) have been incorporated into f-SWNT-COS. f-SWNTs-COS-GTX-p53, f-SWNTs-COS-GTX-lysozyme, f-SWNTs-COS-GTX-FA have been physiochemically characterized for DDS. FT-IR, SEM and TEM analysis confirmed the formation of chemical interaction and polymer coating. FT-IR result clearly confirmed the interaction between f-SWNT and COS. The effective drug release was monitored against cervical cancer (HeLa) cells and Breast Cancer (MCF-7) cells and it was found that all the three drug delivery systems showed significant cytotoxicity. f-SWNTs-COS-GTX-p53 delivery vehicle and its effective cytotoxicity on HeLa cells was further checked with fluorescent activated cell sorter analysis. Our results suggest that the f-SWNTs-COS-GTX-p53 is the most effective delivery vehicle with a controlled release and enhanced cytotoxicity rendered through apoptosis in human cervical cancer (HeLa) cells. These systems can further be used for the delivery of other commercially available anti cancer drugs as well.
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PMID:Polymer functionalized single walled carbon nanotubes mediated drug delivery of gliotoxin in cancer cells. 2472 4

Previously, we showed that Mekk1 translocates to the nucleus, interacts with tumor suppressor protein p53, and co-represses PKD1 transcription via an atypical p53 binding site on the minimal PKD1 promoter (JBC 285:38,818-38,831, 2010). In this study, we report the mechanisms of Mekk1 nuclear transport and p53 binding. Using GFP-linked constitutively active-Mekk1 (CA-Mekk1) and a deletion strategy, we identified a nuclear localization signal (HRDVK) located at amino acid (aa) residues 1,349-1,353 in the C-terminal Mekk1 catalytic domain. Deletion of this sequence in CA-Mekk1 and full-length Mekk1 significantly reduced their nuclear translocation in both HEK293T and COS-1 cells. Using co-immunoprecipitation, we identified an adjacent sequence (GANLID, aa 1,354-1,360) in Mekk1 responsible for p53 binding. Deletion of this sequence markedly reduced the interaction of Mekk1 with p53. Mekk1 does not appear to affect phosphorylation of Ser15, located in the Mdm2 interaction site, or other Ser residues in p53. However, Mekk1 mediates p53 protein stability in the presence of Mdm2 and reduces p53 ubiquitination, suggesting an interference with Mdm2-mediated degradation of p53 by the ubiquitin-proteasome pathway.
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PMID:Nuclear Localization Signal and p53 Binding Site in MAP/ERK Kinase Kinase 1 (MEKK1). 2601 53


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