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Query: UMLS:C0009443 (cold)
 92,137 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A p53 peptide-specific CTL line was generated through stimulation with autologous monocyte-derived dendritic cells (DC) pulsed with wild-type HLA-A2 binding p53 derived peptides. A p53 peptide-specific CD8(+) CTL line was established from a healthy HLA-A2 positive donor. The CTL line was characterized with respect to specificity, affinity and killing of cell lines derived from p53 mutated spontaneous tumors. The CTL line demonstrated lysis of p53(139-147) pulsed target cells and cold target inhibition experiments as well as antibody blocking confirmed that the killing was epitope-specific, HLA-A2 restricted and dependent on CD8-binding. Interestingly, the affinity of the CTL line was only in the micromole per liter range and target cells pulsed with less than 0.01 microM peptide were not recognized. Furthermore, 3 HLA-A2(+) p53 mutated tumor cell lines were efficiently lysed by the CTL line, indicating that this novel p53 peptide epitope is endogenously processed and presented by the HLA-A2 molecules of the tumor cells. In conclusion, CTL reactivity towards a wild-type p53 peptide was revealed through induction with DC pulsed with a pool of HLA-A2 binding p53 peptides. In addition, the CTL line, which expressed relatively low affinity for the HLA-A2/peptide complex, was able to kill 3 different HLA-A2(+) p53 mutated tumor cell lines. The present and our previous observations expand the number of p53-derived peptides suitable for vaccination protocols for cancer patients with p53 positive tumors.
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PMID:A HLA-A2 restricted human CTL line recognizes a novel tumor cell expressed p53 epitope. 1199 47

Cancer is a multigenic disorder involving mutations of both tumor suppressor genes and oncogenes. A large body of preclinical data, however, has suggested that cancer growth can be arrested or reversed by treatment with gene transfer vectors that carry a single growth inhibitory or pro-apoptotic gene or a gene that can recruit immune responses against the tumor. Many of these gene transfer vectors are modified viruses that retain the capability of the virus for efficient gene delivery but are safer than the native virus due to modifications that eliminate or alter one or more essential viral functions. The field of viral-based gene transfer vectors for the treatment of cancer has now entered the final stage of clinical testing prior to possible product approvals. Three viral vectors are currently undergoing this Phase III or Phase II/III clinical testing for cancer treatment. All three of these vectors are based on adenovirus, a common human virus that in its native state can cause cold or flu-like symptoms. In two of these vectors, genes essential for viral replication have been replaced with the wild-type p53 tumor suppressor gene, a gene that is deleted or mutated in over 50% of human cancers and which, when transferred into tumor cells, can induce tumor cell death. The third vector retains more of the natural adenoviral functions and relies on replication in tumor cells to induce cell killing. These three vectors represent two of the approaches now being taken to develop viral-based gene transfer vectors for cancer treatment. Additional approaches include the transfer of genes capable of converting non-toxic prodrugs into toxic forms, using anti-angiogenic gene transfer to block the formation of tumor blood vessels, inhibiting the activity of oncogenes through blocks to transcription or translation, stimulating the body's own immune system with immunomodulatory genes, and "cancer vaccination" with genes for tumor antigens. The data derived to date from clinical trials with viral-based vector systems are promising. The vectors have been generally well-tolerated without the severe toxicities common to standard cancer treatments. Many of these vectors have been demonstrated to have anti-tumor activity in a clinical setting and to lead to tumor regressions or to reductions in the rate of tumor growth. Furthermore, the safety profile of these vector systems has allowed for their clinical testing in combination with conventional cancer treatments to determine their benefit in multi-modality therapy. As part of their clinical development, all three of the vectors in Phase III and Phase II/III clinical trials are being tested for their benefit in combination with chemotherapy in randomized trials. The field is also looking to future product opportunities with improvements that will further increase potency, safety, and/or ease of administration. These developments may expand the number of cells that are susceptible to infection or may target the vector to particular tumor types following an intravenous administration. Some of these approaches are already in clinical testing. Additional opportunities may utilize multigene strategies to target multiple pathways in cancer cells or expand the use of cytotoxic or cytostatic gene transfer in combination with immunotherapy.
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PMID:Viral-mediated gene transfer for cancer treatment. 1202 58

In an effort to search for genes responsible for cell growth arrest and/or apoptosis associated with p53 signaling pathways, we profiled a human lung carcinoma line H1299, expressing a temperature-sensitive p53 (V138) against Affymetric human U95Av2 GeneChip A, consisting of 12 000 genes. 133 genes were identified that were either induced or repressed in response to p53-dependent cell growth arrest and apoptotic conditions. Among them, the beta1 subunit, but not other subunits of the AMP-activated protein kinase (AMPK) was strongly induced. The p53 consensus binding site search in the AMPK-beta1 promoter and the first intron identified four such putative sites. However, p53 failed to bind to any of these sites as assayed by in vitro gel retardation and in vivo chromatin immunoprecipitation. Furthermore, northern analysis showed that induction of this gene is independent of p53, as increased expression of the gene was observed in p53 null H1299/Neo control cells when the temperature was shifted to 32 degrees C. Moreover, a DNA damaging agent, etoposide, also induced beta1 subunit expression in multiple human tumor cells, regardless of p53 status. Thus, the beta1 subunit of AMPK is not a p53 downstream target gene, but can be induced by cold shock or the chemotherapeutic drug, etoposide in a p53-independent manner. To determine the biological significance of AMPK-beta1 induction, we over-expressed the gene in two tumor cell lines, H1299 and U2-OS. In both lines, forced AMPK-beta1 expression inhibits tumor cell growth, suggesting that AMPK-beta1 induction may facilitate stress-induced growth inhibition and cell killing.
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PMID:AMPK-beta1 subunit is a p53-independent stress responsive protein that inhibits tumor cell growth upon forced expression. 1277 Oct 25

The wild-type p53 protein can be driven into a conformation corresponding to that adopted by structural mutant forms by heterodimerization with a mutant subunit. To seek partially folded states of the wild-type p53 core domain (p53C) we used high hydrostatic pressure (HP) and subzero temperatures. Aggregation of the protein was observed in parallel with its pressure denaturation at 25 and 37 degrees C. However, when HP experiments were performed at 4 degrees C, the extent of denaturation and aggregation was significantly less pronounced. On the other hand, subzero temperatures under pressure led to cold denaturation and yielded a non-aggregated, alternative conformation of p53C. Nuclear magnetic resonance (1H15N-NMR) data showed that the alternative p53C conformation resembled that of the hot-spot oncogenic mutant R248Q. This alternative state was as susceptible to denaturation and aggregation as the mutant R248Q when subjected to HP at 25 degrees C. Together these data demonstrate that wild-type p53C adopts an alternative conformation with a mutant-like stability, consistent with the dominant-negative effect caused by many mutants. This alternative conformation is likely related to inactive forms that appear in vivo, usually driven by interaction with mutant proteins. Therefore, it can be a valuable target in the search for ways to interfere with protein misfolding and hence to prevent tumor development.
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PMID:Conversion of wild-type p53 core domain into a conformation that mimics a hot-spot mutant. 1452 28

We have investigated the mechanisms of induction of apoptosis by the antineoplastic ether lipid ET-18-OCH3 (ALP) in sensitive S49wt mouse lymphoma cells and ALP-resistant S49ar variants, both with wild-type p53, and in related L1210 cells with mutated p53. Ether lipid-resistant S49ar cells were cross-resistant to extracellular stress factors (cold shock, heat shock, H2O2, dimethylsulfoxide) and to radiation-induced apoptosis but not to physiological apoptotic signals (dexamethasone, growth factor deprivation, thapsigargin, C2-ceramide) and expressed similar levels of the apoptosis-regulating proteins Bcl-2, Bcl-X, Bax, Bad and Bak as did the parent S49wt cells. The uptake of [3H]-ALP was strongly reduced in the stress-resistant cells but this was not associated with significant differences in membrane cholesterol:phospholipid content nor in membrane microviscosity. In S49ar cells the activity of the antioxidant enzyme glutathione peroxidase (GSH-Px) was increased 4-fold and depletion of glutathione with the drug L-buthionine-S-R-sulfoximine (L-BSO) lowered the resistance of S49ar cells to ALP, stress factors and ionising radiation. The results indicate that ether lipids induce apoptosis by imposing a special form of physico-chemical stress, mediated by reactive oxygen species but independent of p53 status. The capacity of glutathione-dependent anti-oxidant defence appeared an important and shared determinant of the sensitivity to ether lipids, several types of extracellular stress and ionising radiation.
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PMID:Signalling steps in apoptosis by ether lipids. 1463 26

Early graft dysfunction due to ischemia reperfusion injury remains a major clinical challenge in liver transplantation. Because apoptosis may contribute to graft dysfunction, we studied whether transient inhibition of p53 is capable of improving graft quality by reducing apoptotic cell death. Rat livers were harvested and stored for 24 hours or 48 hours in a 4 degrees C solution containing either pifithrin-alpha (PFT-alpha), a specific p53-inhibitor, or the vehicle dimethyl-sulfoxide. Storage was followed by 2-hour reperfusion with 37 degrees C Krebs-Henseleit buffer in an isolated liver perfusion system. Besides caspase-3 activation, apoptosis was quantified using fluorescence microscopy and hematoxylin-eosin histology. Trypan blue allowed for assessment of cell membrane damage, indicating both secondary apoptosis and primary necrosis. Bile flow, oxygen consumption, K(+)-excretion and enzyme release served as indicators of overall graft quality. Upon 2-hour reperfusion, livers developed procaspase activation as well as a mixture of apoptotic and necrotic cell death, representing necrapoptosis. In livers that had been stored for 48 hours, necrapoptotic injury was more pronounced compared with that after 24-hour storage. PFT-alpha effectively attenuated caspase activation as well as hepatocellular apoptosis and necrosis. Attenuation of both modes of cell death by PFT-alpha was associated with improved liver function, metabolism, and integrity. Experiments with the caspase inhibitor z-VAD-fmk confirmed that apoptosis is one mode of cell death in cold ischemia reperfusion. In conclusion, inhibition of p53-dependent apoptosis by PFT-alpha reduces hepatic preservation-reperfusion injury and improves primary organ function and metabolism. Fortification of the preservation solution with PFT-alpha may represent a promising and easily applicable approach to mitigate reperfusion injury in liver transplants.
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PMID:Improvement of rat liver graft quality by pifithrin-alpha-mediated inhibition of hepatocyte necrapoptosis. 1518 96

Pten is an important phosphatase, suppressing the phosphatidylinositol-3 kinase/Akt pathway. Here, we generated adipose-specific Pten-deficient (AdipoPten-KO) mice, using newly generated Acdc promoter-driven Cre transgenic mice. AdipoPten-KO mice showed lower body and adipose tissue weights despite hyperphagia and enhanced insulin sensitivity with induced phosphorylation of Akt in adipose tissue. AdipoPten-KO mice also showed marked hyperthermia and increased energy expenditure with induced mitochondriagenesis in adipose tissue, associated with marked reduction of p53, inactivation of Rb, phosphorylation of cyclic AMP response element binding protein (CREB) and increased expression of Ppargc1a, the gene that encodes peroxisome proliferative activated receptor gamma coactivator 1 alpha. Physiologically, adipose Pten mRNA decreased with exposure to cold and increased with obesity, which were linked to the mRNA alterations of mitochondriagenesis. Our results suggest that altered expression of adipose Pten could regulate insulin sensitivity and energy expenditure. Suppression of adipose Pten may become a beneficial strategy to treat type 2 diabetes and obesity.
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PMID:Enhanced insulin sensitivity, energy expenditure and thermogenesis in adipose-specific Pten suppression in mice. 1593 75

Cyclin G1 (CG1) was identified as a p53-transactivated target gene, and yet its physiological and pathological roles have been unclear. Here, we demonstrate that CG1 is translocated from cytoplasm to the nuclei of neurons in response to variety of injuries. In the normal matured rodent brain, CG1 immunoreactivity was hardly observed; however, some brain injuries exhibited intense CG1 immunoreactivity in the nuclei of the damaged neurons. Transient common carotid artery occlusion (CCAO) in the gerbil showed strong CG1-like immunoreactivity in the hippocampal CA1 neurons, and permanent middle cerebral artery occlusion (MCAO) in the mouse showed strong CG1-like immunoreactivity in the nuclei of neurons located in the ischemic brain regions. TUNEL staining did not exactly overlap with the CG1-positive cells, but overlapped highly with Fluoro-Jade B staining, a degeneration marker. Brain trauma caused by knife cut, cold injury, and kinate injection also showed CG1 accumulation in the neuronal nuclei located near the injury site. These observations were obtained in p53-deficient mice as well, suggesting that the accumulation of CG1 in the injured neurons is p53-independent. A similar nuclear translocation of endogenous CG1 was confirmed in a primary culture of cortical neurons when a toxic level of N-methyl-D-aspartate (NMDA) was applied. These results demonstrate that nuclear translocation of CG1 from cytoplasmic region occurs in damaged and degenerating neurons in a p53-independent manner, and the CG1 nuclear staining could be a good marker for the neurons received fatal damages.
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PMID:The p53-independent nuclear translocation of cyclin G1 in degenerating neurons by ischemic and traumatic insults. 1586 37

The p53 tumor suppressor protein is a transcription factor that mediates the cell's response to various kinds of stress by preventing cell division and/or inducing apoptosis. p53 gene mutations have been detected in nearly 50% of human cancers. These gene aberrations are mostly missense point mutations located predominantly in the central DNA-binding domain. In addition to the classical inactivating mutations, there are also dominant-negative, gain-of-function, temperature-sensitive, and cold-sensitive, discriminating, superactive p53 mutations, and some mutations that do not inactivate p53 activity. Several approaches have been developed for detection and analyses of p53 mutations: first, immunochemical methods have been developed to detect p53 protein levels; second, molecular analyses targeting changes in DNA structure are utilized; and third, functional assays are used to explore the biological properties of the p53 protein. Functional analysis of separated alleles in yeast targets the transactivation capability of the p53 protein expressed in yeast cells. This method uses p53 mRNA isolated from cells and tissues to produce a p53 product by RT-PCR. This method has undergone continuous improvement and now serves as a powerful tool for distinguishing various functional types of p53 mutations. Understanding the exact impact of p53 mutation on its function is an important prerequisite for establishment of efficient anti-cancer therapies.
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PMID:Functional analysis of p53 tumor suppressor in yeast. 1613 27

As a clinical entity, breast cancer appears to be a series of subforms, each with a relatively specific molecular phenotype. Among the characteristics that differentiate these subforms are sex hormone receptor expression, HER2 expression, p53 mutation, high-grade histopathology, and particular gene expression array patterns. Sporadic basal-like breast cancer is one such form. It is a relatively common, high-grade, hormone receptor and HER2-expression-negative, p53 mutation-bearing tumor and is particularly lethal. Although wild type for BRCA1, it is a sporadic phenocopy of most cases of BRCA1(/) breast cancer. Not only do the cells of the two tumors resemble one another with respect to the above-noted characteristics, they also share a defect in the maintenance of an intact, inactive X chromosome (Xi). Other high-grade and most low-grade tumors are rarely defective at Xi. This evidence suggests that an Xi defect contributes to the evolution of both sporadic and BRCA1(/) basal-like breast tumors.
Cold Spring Harb Symp Quant Biol 2005
PMID:Abnormalities of the inactive X chromosome are a common feature of BRCA1 mutant and sporadic basal-like breast cancer. 1686 42


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