Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of p53 to induce apoptosis plays an important role in tumor suppression. Here, we describe a previously unknown posttranslational modification of the DNA-binding domain of p53. This modification, acetylation of lysine 120 (K120), occurs rapidly after DNA damage and is catalyzed by the MYST family acetyltransferases hMOF and TIP60. Mutation of K120 to arginine, as occurs in human cancer, debilitates K120 acetylation and diminishes p53-mediated apoptosis without affecting cell-cycle arrest. The K120R mutation selectively blocks the transcription of proapoptotic target genes such as BAX and PUMA while the nonapoptotic targets p21 and hMDM2 remain unaffected. Consistent with this, depletion of hMOF and/or TIP60 inhibits the ability of p53 to activate BAX and PUMA transcription. Furthermore, the acetyllysine 120 (acetyl-K120) form of p53 specifically accumulates at proapoptotic target genes. These data suggest that K120 acetylation may help distinguish the cell-cycle arrest and apoptotic functions of p53.
Mol Cell 2006 Dec 28
PMID:Acetylation of the p53 DNA-binding domain regulates apoptosis induction. 1718 82

Gene therapy is one of the approaches used to treat lung cancer. The benefit of cancer gene therapy is that different types of tumors can be selectively targeted by tumor-specific expression of therapeutic genes that include an apoptosis gene to destroy the tumor. Previously, we described a promoter (TTS promoter) that we designed that is specifically targeted to lung cancer cells but not to other types of cancer or normal cells including stem cells. In this pursuit, we further characterize the specificity of the TTS promoter in four types of lung cancer cells (squamous cell lung carcinoma, pulmonary adenocarcinoma, small-cell lung carcinoma, large-cell lung carcinoma). The TTS promoter is highly active only in pulmonary adenocarcinoma cells but not in the other three types of lung cancer cells. The specificity seems to be derived from transcription factor thyroid transcription factor 1-associating cofactors that affect human surfactant protein A1 promoter activity in pulmonary adenocarcinoma. We inserted the proapoptotic gene Bcl-2-associated X protein (Bax) into the TTS promoter (TTS/Bax). The TTS/Bax selectively causes BAX expression and cell death in pulmonary adenocarcinoma but not in other cells. Cell death caused by the BAX expression was also observed in pulmonary adenocarcinoma that is resistant to the anticancer drug gefitinib (epidermal growth factor receptor tyrosine kinase inhibitor). BAX expression and cell death can be suppressed by dexamethasone (a glucocorticoid) treatment through negative glucocorticoid elements in the TTS promoter. Here we report a drug-controllable TTS/Bax system targeting pulmonary adenocarcinoma.
Mol Cancer Ther 2007 Jan
PMID:Pulmonary adenocarcinoma-targeted gene therapy by a cancer- and tissue-specific promoter system. 1723 83

Ansamycin antibiotics that target heat shock protein 90 function are being developed as anticancer agents but are also known to be dose limiting in patients due to hepatotoxicity. Herein, to better understand how the normal tissue toxicity of geldanamycins could be ameliorated to improve the therapeutic index of these agents, we examined the interactions of 17-allylamino-17-demethoxygeldanamycin (17AAG) and the secondary bile acid deoxycholic acid (DCA) in hepatocytes and fibroblasts. DCA and 17AAG interacted in a greater than additive fashion to cause hepatocyte cell death within 2 to 6 h of coadministration. As single agents DCA, but not 17AAG, enhanced the activity of extracellular signal-regulated kinase 1/2, AKT, c-Jun NH(2)-terminal kinase 1/2 (JNK1/2), and p38 mitogen-activated protein kinase (MAPK). Combined exposure of cells to DCA and 17AAG further enhanced JNK1/2 and p38 MAPK activity. Inhibition of JNK1/2 or p38 MAPK, but not activator protein-1, suppressed the lethality of 17AAG and of 17AAG and DCA. Constitutive activation of AKT, but not MAPK/extracellular signal-regulated kinase kinase 1/2, suppressed 17AAG- and DCA-induced cell killing and reduced activation of JNK1/2. DCA and 17AAG exposure promoted association of BAX with mitochondria, and functional inhibition of BAX or caspase-9, but not of BID and caspase-8, suppressed 17AAG and DCA lethality. DCA and 17AAG interacted in a greater than additive fashion to promote and prolong the generation of reactive oxygen species (ROS). ROS-quenching agents, inhibition of mitochondrial function, expression of dominant-negative thioredoxin reductase, or expression of dominant-negative apoptosis signaling kinase 1 suppressed JNK1/2 and p38 MAPK activation and reduced cell killing after 17AAG and DCA exposure. The potentiation of DCA-induced ROS production by 17AAG was abolished by Ca(2+) chelation and ROS generation, and cell killing following 17AAG and DCA treatment was abolished in cells lacking expression of PKR-like endoplasmic reticulum kinase. Thus, DCA and 17AAG interact to stimulate Ca(2+)-dependent and PKR-like endoplasmic reticulum kinase-dependent ROS production; high levels of ROS promote intense activation of the p38 MAPK and JNK1/2 pathways that signal to activate the intrinsic apoptosis pathway.
Mol Cancer Ther 2007 Feb
PMID:17-Allylamino-17-demethoxygeldanamycin enhances the lethality of deoxycholic acid in primary rodent hepatocytes and established cell lines. 1730 59

Selenium is an essential trace element in conventional tissue culture media to guarantee adequate biosynthesis of selenoprotein in cellular antioxidant system to protect the cells from oxidative damage and apoptosis. This study investigated the effect of selenium, in the form of sodium selenite (SS), on developmental ability and quality of in vitro produced porcine parthenotes. For this, parthenogenetic presumptive diploid zygotes were produced by electroactivation and cultured in the absence or presence of SS at different concentrations (0, 2.5, 25, 250 ng/ml) in a serum-free defined culture medium supplemented with polyvinyl alcohol (PVA) or bovine serum albumin (BSA). Results showed that, development rate of 2-4 cell stage parthenotes to blastocyst and their cell number was increased while TUNEL index was decreased, in a dose-dependent manner, when SS was supplemented to NCSU23 + PVA. Interestingly, the blastocyst rate and their quality approached to those cultured in NCSU23 + BSA (P < 0.05), thereby suggesting PVA + 25 ng/ml SS to be a partial replacement of BSA. In the presence of PVA, supplementation of SS at a concentration of 25 ng/ml did not improve the cleavage rate of in vitro matured oocytes but there was significant improvement in the blastocyst rate (45.4 +/- 8.8% vs. 12.7 +/- 4.8%), total nuclei number (42.1 +/- 3.5 vs. 31.3 +/- 2.9) and inner cell mass (ICM) rate (29.4 +/- 1.5% vs. 21.3 +/- 1.2%) and decrease in TUNEL index (5.6 +/- 0.5 vs. 12.9 +/- 1.3) compared to nonsupplemented controls. The SS supplementation also decreased the BAX:BCL-xL transcript ratio, increased the expression of ERK1/2 and glutathione peroxidase (GPX) and reduced the level of Caspase 3 proteins (P < 0.05). These data thus suggest that SS improves the development rate and quality of porcine parthenotes by preventing oxidative damage and apoptosis.
Mol Reprod Dev 2007 Nov
PMID:Selenium improves the developmental ability and reduces the apoptosis in porcine parthenotes. 1734 38

The use of shRNA for knockdown of gene expression is a powerful method. In addition to transient transfection of RNA oligonucleotides, various DNA-based vectors that express short hairpin RNAs have been successfully used for efficient depletion of gene products. Replication-defective retrovirus and adenovirus (Ad) vectors have also gained wide usage. The extension of shRNA technology to replication-competent Ad would be desirable to investigate the role of various cellular genes in Ad replication. This approach is hampered because the effect of shRNA is neutralized by the Ad VA-RNA that is expressed at late stages after infection, and the infected cells are killed prior to significant depletion of some long-lived target gene products. We have constructed replication-competent Ad vectors for the depletion of the pro-apoptotic proteins BAX and BAK. We have modified a replication-defective Ad multivalent shRNA expression vector developed by Welgen, Inc. In our vector design, the multivalent shRNA expression cassette is contained in the E1B region. Additionally, we have incorporated a temperature-sensitive mutation in the viral DBP gene (ts125). The use of this vector has resulted in efficient depletion of critical cellular apoptotic modulators, BAX and BAK. This vector may be useful to study the role of various cellular genes in Ad-induced apoptosis and viral replication.
Methods Mol Med 2007
PMID:Temperature-sensitive replication-competent adenovirus shRNA vectors to study cellular genes in virus-induced apoptosis. 1740 Nov 68

This paper describes a method allowing correcting false gene expression measured on highly degraded RNA using real-time quantitative reverse transcription-polymerase chain reaction (RTQ-PCR). RNA was isolated from different models (in vitro cell lines, in vivo models of human and dog) and different tissue types. In vitro RNA degradation and modeling of in vivo degradation were applied on intact and degraded total RNA. Gene expression (eg, Bcl-2, GAPDH, PGK, PSME3, RAB2, BAX) was measured using RTQ-PCR. 18S rRNA proved to be the most constant house-keeping gene. Less than 10-fold degraded RNA can be quantified correctly when using 18S rRNA for normalization purposes. Higher-fold degraded RNA can be quantified correctly up to a precision that is comparable to RTQ-PCR measurements on intact RNA when simulating the RNA-species and tissue-specific degradation kinetic.
Diagn Mol Pathol 2007 Mar
PMID:Correcting false gene expression measurements from degraded RNA using RTQ-PCR. 1747 Nov 57

In vitro production of porcine embryos has become routine in most laboratories but the yield and quality of the resultant blastocysts remains sub-optimal. Phytohemagglutinin (PHA) is an N-acetylgalactosamine/galactose sugar-specific lectin with a wide variety of biological activities including mitogenesis, mediation of cell recognition and agglutination of cells. This study was therefore, designed to investigate the effect of PHA on the preimplantation development and quality of parthenogenetic, somatic cell nuclear transferred (SCNT) and in vitro fertilized (IVF) porcine embryos cultured in the absence or presence of PHA. Analysis showed that, supplementation of PHA significantly improved the blastocyst rate of parthenogenetic (70.6 +/- 0.2 vs. 51.4 +/- 0.6%) and SCNT (27.7 +/- 1.7 vs. 12.5 +/- 0.3%) embryos but not IVF embryos (25.0 +/- 14.3 vs. 20.1 +/- 12.7%). Nonetheless, PHA-treated blastocysts had higher hatching ability and contained higher cell number than control blastocysts in all the groups (P < 0.05). TUNEL labeling revealed that blastocysts cultured in the presence of PHA were less predisposed to biochemical apoptosis and showed lower indices of TUNEL, fragmentation and total apoptosis than those cultured in the absence of PHA (P < 0.05). Real time qRT-PCR analysis of parthenogenetic blastocysts revealed that PHA decreased the expression ratio of BAX:BCL-xL transcripts. Therefore, our study suggests that PHA improves the blastocyst yield and quality by enhancing blastocyst expansion, hatching and total cell number and decreasing the apoptosis. However, PHA has a differential effect on development rate of IVF derived embryos. These results may represent an approach towards achieving better preimplantation development of porcine embryos in vitro.
Mol Reprod Dev 2007 Dec
PMID:Differential but beneficial effect of phytohemagglutinin on efficiency of in vitro porcine embryo production by somatic cell nuclear transfer or in vitro fertilization. 1747 88

We have examined the mechanisms by which the multinuclear platinum chemotherapeutic BBR3610 kills human colon cancer cells. BBR3610 more efficiently killed HCT116, DLD1, SW480, and HT29 cells than BBR3464, cisplatin, or oxaliplatin. The amount of platinum uptake per cell and its incorporation into DNA were identical for BBR3464 and BBR3610. BBR3610 lethality (IC(75)) was unaltered comparing HCT116 wild-type and p53-/- cells, was reduced in p21-/- cells, and was enhanced in K-RAS D13 null cells. Small molecule or molecular inhibition of epidermal growth factor receptor (ERBB1) or phosphatidyl inositol 3 kinase (PI3K) enhanced BBR3610 toxicity in HCT116, DLD1, and SW480 cells. Small molecule or molecular inhibition of caspase 8 function abolished the toxicity of BBR3610 and of BBR3610 + ERBB1 inhibitor treatments, whereas inhibition of caspase 9 suppressed the ability of ERBB1 inhibitors to enhance BBR3610 lethality. Treatment with BBR3610 reduced AKT activity; the expression of dominant-negative AKT enhanced and expression of constitutively active AKT suppressed, respectively, the toxicity of BBR3610 and of BBR3610 + ERBB1 inhibitor treatments. Treatment with BBR3610 reduced expression of c-FLIP-s and MCL-1, levels that were maintained in cells expressing constitutively active AKT. Overexpression of c-FLIP-s or loss of BID function suppressed BBR3610 toxicity, whereas overexpression of XIAP or Bcl-xL suppressed the potentiation of cell killing by ERBB1 inhibitors. Collectively, our data argue that BBR3610 promotes cell killing via a caspase 8-dependent mechanism, which can be enhanced by ERBB1/PI3K inhibitors that promote additional BBR3610-dependent cell killing via activation of BAX and caspase 9.
Mol Pharmacol 2007 Sep
PMID:Low-dose BBR3610 toxicity in colon cancer cells is p53-independent and enhanced by inhibition of epidermal growth factor receptor (ERBB1)-phosphatidyl inositol 3 kinase signaling. 1757 96

Piracetam is the derivate of gamma-aminobutyric acid, which improves the cognition,memory,consciousness, and is widely applied in the clinical treatment of brain dysfunction. In the present experiments, we study the effects of piracetam on chronic cerebral hypoperfused rats and observe its influence on amino acids, synaptic plasticity in the Perforant path-CA3 pathway and apoptosis in vivo. Cerebral hypoperfusion for 30 days by occlusion of bilateral common carotid arteries induced marked amnesic effects along with neuron damage, including: (1) spatial learning and memory deficits shown by longer escape latency and shorter time spent in the target quadrant; (2) significant neuronal loss and nuclei condensation in the cortex and hippocampus especially in CA1 region; (3) lower induction rate of long term potentiation, overexpression of BAX and P53 protein, and lower content of excitatory and inhibitory amino acids in hippocampus. Oral administration of piracetam (600 mg/kg, once per day for 30 days) markedly improved the memory impairment, increased the amino acid content in hippocampus, and attenuated neuronal damage. The ability of piracetam to attenuate memory deficits and neuronal damage after hypoperfusion may be beneficial in cerebrovascular type dementia.
Cell Mol Neurobiol 2008 Jun
PMID:Piracetam improves cognitive deficits caused by chronic cerebral hypoperfusion in rats. 1771 May 36

Amino acids play a multitude of roles during early embryonic development and have been demonstrated to facilitate improved development of in vivo or in vitro fertilized and parthenogenetic embryos in several species. However, review of emerging literatures, shows that culture milieu of cloned embryos might be different from those of in vitro fertilized embryos. This study therefore, evaluated the effect of nonessential amino acids (NEAA) on yield and quality of porcine embryos produced by somatic cell nuclear transfer (SCNT) and compared them with parthenogenetic embryos as control. Analysis showed that, supplementation of NEAA to culture medium significantly improved the blastocyst rate of parthenogenetic (38.9 +/- 8.8 vs. 27.5 +/- 9.0%) as well as SCNT (22.5 +/- 2.2 vs. 13.8 +/- 3.4%) embryos although cleavage rates were not different (P < 0.05). These blastocysts also had higher hatching ability and contained higher cell number than control blastocysts (P < 0.05). TUNEL labeling revealed that blastocysts cultured in the presence of NEAA were less predisposed to biochemical apoptosis and showed lower indices of TUNEL, fragmentation, and total apoptosis than those cultured in the absence of NEAA (P < 0.05). Real-time qRT-PCR analysis further revealed that NEAA decreased the expression ratio of BAX:BCL-xL and enhanced the relative abundance of IGF2 transcripts. Therefore, our study suggests that NEAA improves the yield and quality of cloned porcine embryos by enhancing blastocyst expansion, hatching, and total cell number and decreasing the apoptosis by positively modulating the expression of embryo survival related genes, similar to those reported for in vivo or in vitro fertilized embryos. Nonessential amino acids improve the yield and quality of cloned and parthenogenetic porcine embryos and modulate the expression of embryo survival related genes.
Mol Reprod Dev 2008 Apr
PMID:Role of nonessential amino acids on porcine embryos produced by parthenogenesis or somatic cell nuclear transfer. 1788 65


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