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 spindle checkpoint that monitors kinetochore-microtubule attachment has been implicated in tumorigenesis; however, the relation between the spindle checkpoint and cell death remains obscure. In BUB1-deficient (but not MAD2-deficient) cells, conditions that activate the spindle checkpoint (i.e., cold shock or treatment with nocodazole, paclitaxel, or 17-AAG) induced DNA fragmentation during early mitosis. This mitotic cell death was independent of caspase activation; therefore, we named it caspase-independent mitotic death (CIMD). CIMD depends on p73, a homologue of p53, but not on p53. CIMD also depends on apoptosis-inducing factor and endonuclease G, which are effectors of caspase-independent cell death. Treatment with nocodazole, paclitaxel, or 17-AAG induced CIMD in cell lines derived from colon tumors with chromosome instability, but not in cells from colon tumors with microsatellite instability. This result was due to low BUB1 expression in the former cell lines. When BUB1 is completely depleted, aneuploidy rather than CIMD occurs. These results suggest that cells prone to substantial chromosome missegregation might be eliminated via CIMD.
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PMID:BUB1 mediation of caspase-independent mitotic death determines cell fate. 1762 Apr 10

PCR is widely employed as the initial DNA amplification step for genetic testing. However, a key limitation of PCR-based methods is the inability to selectively amplify low levels of mutations in a wild-type background. As a result, downstream assays are limited in their ability to identify subtle genetic changes that can have a profound impact in clinical decision-making and outcome. Here we describe co-amplification at lower denaturation temperature PCR (COLD-PCR), a novel form of PCR that amplifies minority alleles selectively from mixtures of wild-type and mutation-containing sequences irrespective of the mutation type or position on the sequence. We replaced regular PCR with COLD-PCR before sequencing or genotyping assays to improve mutation detection sensitivity by up to 100-fold and identified new mutations in the genes encoding p53, KRAS and epidermal growth factor in heterogeneous cancer samples that had been missed by the currently used methods. For clinically relevant microdeletions, COLD-PCR enabled exclusive amplification and isolation of the mutants. COLD-PCR will transform the capabilities of PCR-based genetic testing, including applications in cancer, infectious diseases and prenatal identification of fetal alleles in maternal blood.
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PMID:Replacing PCR with COLD-PCR enriches variant DNA sequences and redefines the sensitivity of genetic testing. 1840 29

The spindle checkpoint, which monitors kinetochore-microtubule attachment, is required for high fidelity of chromosome transmission. A failure in this mechanism causes aneuploidy, thereby promoting progression to tumorigenesis. However, the cell death mechanism that prevents the aneuploidy caused by failure of the spindle checkpoint is yet unknown. We have recently identified a novel type of mitotic cell death, which we term caspase-independent mitotic death (CIMD). In BUB1-deficient (but not MAD2-deficient) cells, CIMD is induced by conditions that activate the spindle checkpoint (i.e., cold shock or treatment with nocodazole, paclitaxel or 17-AAG [17-allylaminogeldanamycin]). CIMD depends on p73, a homolog of p53, but not on p53. It also depends on the apoptosis-inducing factor (AIF) and endonuclease G (Endo G), which are effectors of caspase-independent cell death. When BUB1 is completely depleted, aneuploidy occurs instead of CIMD. We propose that CIMD can be the cell death mechanism that protects cells from aneuploidy by inducing the death of cells prone to substantial chromosome missegregation. Our study also shows that previous evaluations of the spindle checkpoint activity in mutant or cancer cells by monitoring mitotic index could be misleading.
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PMID:Caspase-independent mitotic death (CIMD). 1841 23

As the incidence and length of spaceflight increases, the need to administer pharmacological agents to crew members may become greater. The final goal is to predict the therapeutic or toxic effects of drugs, especially those with a low therapeutic index, during spaceflight. The liver is central to systemic metabolism, therefore, various drugs rely on hepatic metabolism by cytochrome P450 (CYP). The function of individual CYP enzymes is diverse because they are subject to different regulatory mechanisms and substrate specificity. Because spaceflight may be a stressor and influence each CYP expression individually, the purpose of the present study was to measure the expression of 11 CYP genes and protein distribution in the liver of rats after spaceflight, using real-time polymerase chain reaction and immunohistochemistry, respectively. The gene and protein expression of stress-related proteins such as cold-inducible RNA binding protein (Cirp), heat shock protein 70 (HSP70), HSP90 and the p53 tumor suppressor gene, were also determined. CYP4A1and Cirp gene expression was significantly increased whereas HSP90 and p53 gene expression was significantly decreased in the flight group than in the ground control. Combined with histology, it is concluded that the effects of spaceflight on the liver may be similar to mild cold stress or fasting.
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PMID:Analysis of gene and protein expression of cytochrome P450 and stress-associated molecules in rat liver after spaceflight. 1880 Oct 74

Malignant astrocytomas are highly invasive brain tumors that portend poor prognosis and dismal survival. Mouse models that genetically resemble the human malignancy provide insight into the nature and pathogenesis of these cancers. We previously reported tumor suppressor mouse models based on conditional inactivation of human astrocytoma-relevant genes p53, Nf1, and Pten. These mice develop, with full penetrance, varying grades of astrocytic malignancy that recapitulate the human condition histologically and molecularly. Our studies indicate a central role for neural stem cells and stem-cell-like cancer cells in tumor initiation and progression. These mouse models thus represent powerful tools for investigating various aspects of tumor development that otherwise cannot be explored in humans. Further studies will provide a better understanding of the biology of these tumors and will hopefully pave the way for more effective therapeutic approaches for these devastating diseases.
Cold Spring Harb Symp Quant Biol 2008
PMID:Neural and cancer stem cells in tumor suppressor mouse models of malignant astrocytoma. 1902 44

Senescence and apoptosis programs governed by the Rb and p53 signaling networks can counter tissue stem cell self-renewal. A master regulator of Rb and p53 is the INK4-ARF (CDKN2A/B) locus that encodes two CDK inhibitors, p16(INK4A) and p15(INK4B), that maintain Rb in its active, hypophosphorylated form, and p14(ARF) (p19(Arf) in mice), that inhibits Mdm2 and activates p53. The INK4-ARF genes are epigenetically silenced in hematopoietic stem cells but become poised to respond to oncogenic stress as blood cells differentiate. Inactivation of INK4-ARF endows differentiated cells with an inappropriate self-renewal capacity, a defining feature of cancer cells. In BCR-ABL-induced (Philadelphia chromosome-positive [Ph(+)]) leukemias, INK4-ARF deletions frequently occur in clinically aggressive acute lymphoblastic leukemias (Ph(+) ALLs) but are not seen in more indolent Ph(+) chronic myelogenous leukemia (CML) or in CML myeloid blast crisis. Mouse modeling of Ph(+) ALL reveals that Arf inactivation attenuates responsiveness to targeted BCR-ABL kinase inhibitors, enhances the maintenance of leukemia-initiating cells within the hematopoietic microenvironment, and facilitates the emergence of malignant clones that harbor drug-resistant BCR-ABL kinase mutations. Thus, although BCR-ABL mutations typify drug resistance in both CML and Ph(+) ALL, loss of INK4-ARF in Ph(+) ALL enhances disease aggressiveness and undermines the salutary effects of targeted therapy.
Cold Spring Harb Symp Quant Biol 2008
PMID:The INK4-ARF (CDKN2A/B) locus in hematopoiesis and BCR-ABL-induced leukemias. 1902 87

Mammalian cells cultured in vitro are able to recover from cold stress. However, the mechanisms activated during cold stress and recovery are still being determined. We here report the effects of hypothermia on cellular architecture, cell cycle progression, mRNA stability, protein synthesis and degradation in three mammalian cell lines. The cellular structures examined were, in general, well maintained during mild hypothermia (27-32 degrees C) but became increasingly disrupted at low temperatures (4-10 degrees C). The degradation rates of all mRNAs and proteins examined were much reduced at 27 degrees C, and overall protein synthesis rates were gradually reduced with temperature down to 20 degrees C. Proteins involved in a range of cellular activities were either upregulated or downregulated at 32 and 27 degrees C during cold stress and recovery. Many of these proteins were molecular chaperones, but they did not include the inducible heat shock protein Hsp72. Further detailed investigation of specific proteins revealed that the responses to cold stress and recovery are at least partially controlled by modulation of p53, Grp75 and eIF3i levels. Furthermore, under conditions of severe cold stress (4 degrees C), lipid-containing structures were observed that appeared to be in the process of being secreted from the cell that were not observed at less severe cold stress temperatures. Our findings shed light on the mechanisms involved and activated in mammalian cells upon cold stress and recovery.
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PMID:Biochemical insights into the mechanisms central to the response of mammalian cells to cold stress and subsequent rewarming. 1905 67

Cellular senescence is characterized by an irreversible cell cycle arrest that, when bypassed by mutation, contributes to cellular immortalization. Activated oncogenes induce a hyperproliferative response, which might be one of the senescence cues. We have found that expression of such an oncogene, Akt, causes senescence in primary mouse hepatoblasts in vitro. Additionally, AKT-driven tumors undergo senescence in vivo following p53 reactivation and show signs of differentiation. In another in vivo system, i.e., liver fibrosis, hyperproliferative signaling through AKT might be a driving force of the senescence in activated hepatic stellate cells. Senescent cells up-regulate and secrete molecules that, on the one hand, can reinforce the arrest and, on the other hand, can signal to an innate immune system to clear the senescent cells. The mechanisms governing senescence and immortalization are overlapping with those regulating self-renewal and differentiation. These respective control mechanisms, or their disregulation, are involved in multiple pathological conditions including fibrosis, wound healing, and cancer. Understanding extracellular cues that regulate these processes may enable new therapies for these conditions.
Cold Spring Harb Symp Quant Biol 2008
PMID:Implications of cellular senescence in tissue damage response, tumor suppression, and stem cell biology. 1915 Sep 58

Glioblastoma (GBM) is a highly lethal primary brain cancer with hallmark features of diffuse invasion, intense apoptosis resistance and florid necrosis, robust angiogenesis, and an immature profile with developmental plasticity. In the course of assessing the developmental consequences of central nervous system (CNS)-specific deletion of p53 and Pten, we observed a penetrant acute-onset malignant glioma phenotype with striking clinical, pathological, and molecular resemblance to primary GBM in humans. This primary, as opposed to secondary, GBM presentation in the mouse prompted genetic analysis of human primary GBM samples that revealed combined p53 and Pten mutations as the most common tumor suppressor defects in primary GBM. On the mechanistic level, the "multiforme" histopathological presentation and immature differentiation marker profile of the murine tumors motivated transcriptomic promoter-binding element and functional studies of neural stem cells (NSCs), which revealed that dual, but not singular, inactivation of p53 and Pten promotes cellular c-Myc activation. This increased c-Myc activity is associated not only with impaired differentiation, enhanced self-renewal capacity of NSCs, and tumor-initiating cells (TICs), but also with maintenance of TIC tumorigenic potential. Together, these murine studies have provided a highly faithful model of primary GBM, revealed a common tumor suppressor mutational pattern in human disease, and established c-Myc as a key component of p53 and Pten cooperative actions in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal, and tumorigenic potential.
Cold Spring Harb Symp Quant Biol 2008
PMID:Pten and p53 converge on c-Myc to control differentiation, self-renewal, and transformation of normal and neoplastic stem cells in glioblastoma. 1915 Sep 64

PCR is widely employed as the initial DNA amplification step for genetic testing and cancer biomarker detection. However, a key limitation of PCR-based methods, including real-time PCR, is the inability to selectively amplify low levels of variant alleles in a wild-type allele background. As a result, downstream assays are limited in their ability to identify subtle genetic changes that can have a profound impact on clinical decision-making and outcome or that can serve as cancer biomarkers. We developed COLD-PCR (co-amplification at lower denaturation temperature-PCR) [Li, Wang, Mamon, Kulke, Berbeco and Makrigiorgos (2008) Nat. Med. 14, 579-584], a novel form of PCR that amplifies minority alleles selectively from mixtures of wild-type and mutation-containing sequences irrespective of the mutation type or position on the sequence. Consequently, COLD-PCR amplification from genomic DNA yields PCR products containing high-prevalence variant alleles that can be detected. Since PCR constitutes a ubiquitous initial step for almost all genetic analysis, COLD-PCR provides a general platform to improve the sensitivity of essentially all DNA-variation detection technologies including Sanger sequencing, pyrosequencing, single molecule sequencing, mutation scanning, mutation genotyping or methylation assays. COLD-PCR combined with real-time PCR provides a new approach to boost the capabilities of existing real-time mutation detection methods. We replaced regular PCR with COLD-PCR before sequencing or real-time mutation detection assays to improve mutation detection-sensitivity by up to 100-fold and identified novel p53/Kras/EGFR (epidermal growth factor receptor) mutations in heterogeneous cancer samples that were missed by all existing methods. For clinically relevant micro-deletions, COLD-PCR enabled exclusive amplification and isolation of the mutants. COLD-PCR is expected to have diverse applications in the fields of biomarker identification and tracing, genomic instability, infectious diseases, DNA methylation testing and prenatal identification of fetal alleles in maternal blood.
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PMID:COLD-PCR: a new platform for highly improved mutation detection in cancer and genetic testing. 1929 Aug 75


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