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

A cell culture assay has been developed that detects and validates single-nucleotide polymorphisms (SNPs) in genes that populate the p53 pathway. One hundred thirteen EBV-transformed human B-lymphocyte cell lines obtained from a diverse population were employed to measure the apoptotic response to gamma radiation. Each cell line undergoes a reproducible, characteristic frequency of apoptosis, and the response of the population forms a normal distribution around a median of 35.5% apoptosis with a range from 12% to 58% apoptosis. Polymorphisms in the AKT1 and Perp genes significantly affect the frequency of apoptosis. The assay can detect both racial and sexual dimorphisms in these genes and has the ability to demonstrate epistatic relationships within the p53 pathway. The cell lines used in this assay provide biological materials to explore the molecular basis of the polymorphisms.
Cold Spring Harb Symp Quant Biol 2005
PMID:Single-nucleotide polymorphisms in the p53 pathway. 1686 44

The tumor suppressor p53 exerts its effect through transactivation of a wide variety of genes leading to outcomes such as cell cycle arrest or apoptosis. Both p53 protein levels and modification status are thought to play a role in its ability to discriminate between different target genes and, thereby, cell fate. Here, we have determined the contribution of p53 levels to promoter selectivity when ectopically expressed in H1299 cells. Interestingly, p53AIP1, a pro-apoptotic p53 target gene, requires a significantly higher threshold level of p53 for its activation than p21WAF1, a cell cycle arrest gene. We also found that whereas exogenous p73 exhibits similar transcriptional activity to p53 in H1299 cells, the endogenous p73 that accumulates upon DNA damage in HCT116 cells is unable to compensate for p53 function. Quantification of protein expression levels revealed that the basal expression of TAp73 in HCT116 cells is very low and, even after induction by DNA damage, it accumulates to levels that are lower than basal uninduced levels of p53. These results might partially explain why, unlike p53, p73 does not function as a major tumor suppressor.
Cold Spring Harb Symp Quant Biol 2005
PMID:Transcriptional regulation by p53 and p73. 1686 45

The Ink4a-Arf locus encodes two closely wedded tumor suppressor proteins (p16(Ink4a) and p19(Arf)) that inhibit cell proliferation by activating Rb and p53, respectively. With few exceptions, the Arf gene is repressed during mouse embryonic development, thereby helping to limit p53 expression during organogenesis. However, in adult mice, sustained hyperproliferative signals conveyed by somatically activated oncogenes can induce Arf gene expression and trigger a p53 response that eliminates incipient cancer cells. Disruption of this tumor surveillance pathway predisposes to cancer, and inactivation of INK4a- ARF by deletion, silencing, or mutation has been frequently observed in many forms of human cancer. Although it is accepted that much of Arf's tumor-suppressive activity is mediated by p53, more recent genetic evidence has pointed to additional p53- independent functions of Arf, including its ability to inhibit gene expression by a number of other transcription factors. Surprisingly, the enforced expression of Arf in mammalian cells promotes the sumoylation of several Arf-interacting proteins, implying that Arf has an associated catalytic activity. We speculate that transcriptional down-regulation in response to Arf-induced sumoylation may account for Arf's p53-independent functions.
Cold Spring Harb Symp Quant Biol 2005
PMID:p53-Dependent and -independent functions of the Arf tumor suppressor. 1686 46

Lung tumors are usually classified into small-cell lung cancer (SCLC) or non-SCLC (NSCLC) depending on their pathological and histological characteristics. SCLC is defined not only by its characteristic neuroendocrine differentiation, aggressiveness, and metastatic potential, but also by a specific set of genetic aberrations, including the loss of the tumor suppressor genes p53 and Rb1 and the amplification of any member of the Myc family of oncogenes. We have previously described a mouse model of SCLC by somatic conditional disruption of Trp53 and Rb1 genes that closely resembles the human condition. Based on the possibility to study early tumor lesions and to culture and subclone progressed tumors and metastases, we discuss here a strategy to define genotype-phenotype relationships that can explain the underlying biology of lung neuroendocrine tumors. We have found that tumors may be constituted by genetically variant cell populations, which might represent different progression stages. Interestingly, we observed L-myc amplification and Ascl-1 expression in those populations showing neuroendocrine differentiation. Non-neuroendocrine cell populations from the same tumors did not show L-myc amplification nor Ascl-1 expression. We propose that this genetic divergence can play a relevant role in the definition of some phenotypic characteristics like metastasis potential or chemoresistance.
Cold Spring Harb Symp Quant Biol 2005
PMID:Genotype-phenotype relationships in a mouse model for human small-cell lung cancer. 1686 58

Because the pRb pathway is disrupted in most solid human cancers, we have generated genetically engineered mouse cancer models by inactivating pRb function in several cell types, including astrocytes and mammary, prostate, ovarian, and brain choroid plexus epithelia. In every case, proliferation and apoptosis are acutely induced, predisposing to malignancy. Cell type dictates the pathways involved in tumor progression. In the astrocytoma model, we developed strategies to induce events in the adult brain, either throughout the tissue or focally. Both K-Ras activation and Pten inactivation play significant roles in progression. In the prostate model, adenocarcinoma progression depends on Pten inactivation. However, nonautonomous induction of p53 in the mesenchyme leads to evolution of both compartments, with p53 loss occurring in the mesenchyme. Thus, studies in these models continue to identify key tumorigenesis mechanisms. Furthermore, we are hopeful that the models will provide useful preclinical systems for diagnostic and therapeutic development.
Cold Spring Harb Symp Quant Biol 2005
PMID:Deciphering cancer complexities in genetically engineered mice. 1686 64

Deregulation of the cell cycle machinery plays a critical role in tumorigenesis. In particular, functional inactivation of the retinoblastoma protein (pRB) is a key event. pRB's tumor suppressive activity is at least partially dependent on its ability to regulate the activity of the E2F transcription factors. E2F controls the expression of genes that encode the cellular proliferation machinery. E2F can also trigger apoptosis when it is inappropriately expressed. Here we present evidence that E2F acts to directly regulate the Arf/p53 tumor surveillance network. In normal cells, a single member of the E2F family, E2F3, participates in the transcriptional silencing of Arf. In response to oncogenic stress, the activating E2Fs, E2F1, 2, and E2F3A, all associate with Arf and promote its transcription. These findings raise the possibility that E2F acts as a sensor of inappropriate versus normal proliferative signals and determines whether or not the Arf/p53 tumor surveillance network is engaged.
Cold Spring Harb Symp Quant Biol 2005
PMID:Regulation of the Arf/p53 tumor surveillance network by E2F. 1686 67

After 26 years of research and the publication of 38,000 papers, our knowledge of the p53 human tumor suppressor protein is impressive. Over half of all human cancers have mutations in the p53 gene, and the p53 pathway in animal models dramatically regulates the cellular response to ionizing radiation and chemotherapeutic drugs. The ability to translate this knowledge to patient benefit is, however, still in its infancy. The many approaches to determining the status of the p53 pathway in human tumor biopsy samples and the attempts to develop p53-selective therapies are described. A great deal of our knowledge of the p53 system remains incomplete, and the issue of how to best conduct translational research in cancer is debated using the difficulties around the p53 system as an example. The need for a more unified and coordinated approach to critical technological developments and clinical trial protocols is discussed.
Cold Spring Harb Symp Quant Biol 2005
PMID:Exploiting the p53 pathway for the diagnosis and therapy of human cancer. 1686 88

Y-box binding proteins, belonging to a family of multifunctional proteins conserved from bacteria to human, are involved in transcriptional and translational regulation of various genes, mRNA alternative splicing, DNA replication and repair, as well as cell proliferation. A typical Y-box binding protein contains three structure domains, namely the N-terminal domain, the hydrophilic C-terminal domain and the conserved cold shock domain (CSD) which binds strongly to inverted CCAAT box found in different promoters and determines protein function.Y-box binding proteins may play an important physiological role in cell proliferation.For example, the human Y-box protein 1 (YB-1) may be repressed in the oncogenic phosphoinositide 3-kinase (PI3K) pathway. In addition, it may also act as a negative regulator of p53. It has been demonstrated that YB-1 represses transcription of the p53 promoter in a sequence-specific manner using specifically reporter assays. This implies that YB-1 may, in some situations, protect cells from p53-mediated apoptosis, indicating that YB-1 may be a good target for the development of a new therapeutics.The function of Y-box binding protein and its effect on carcinogenesis are summarized in the paper. We hope to further explore the functional roles of Y-box binding protein, and provide some helpful lines and suggestions for tumor control.
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PMID:[Functions of Y-box binding protein and its role in tumorigenicity]. 1696 28

Severe cardiac hypoxia is responsible for significant morbidity and mortality in an emergency setting. Most cardiac hypoxia relates to ischemia and surgical events. Although the ischemic mortality rate and the risks of cardiac surgery have significantly decreased in past decades, myocardial protection still plays a major role in survival of hypoxic injury. Cross adaptation as a physiological regulation for homeostasis can resist injury caused by harmful environmental effects and diseases, including hypothermic adaptation. Treatment with hypothermia has been used for fifty years as a protective mechanism to avoid hypoxic injury. Since cold temperatures can cause damage, it is important to gather physiological data to distinguish protective from injurious temperatures. Although results of temperature trials in clinical practice vary, a critical temperature to resist hypoxic/ischemic injury in heart was found to be around 30 degrees C, suggesting a hypothermia protective threshold. Pretreatment with mild hypothermia can resist subsequent hypoxia/ischemia, implying involvement of cross adaptation in protection. Safeguard hypothermia can directly reduce the build up of harmful metabolites and energy demand in hypoxic tissues, as well as preserve mitochondrial membrane specific proteins beta subunit of F1-ATPase and adenine nucleotide translocase isoform 1. Mechanisms of preservation include inactivation of the p53 related pathways, representing anti-apoptosis, and modification of the mRNA level of succinodehydrogenease, indicating a beneficial effect on the aerobic pathway. Stress proteins are also induced. Resultant cellular adaptations serve to maintain myocardial integrity and improve functional recovery during reoxygenation or reperfusion.
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PMID:Mild hypothermic cross adaptation resists hypoxic injury in hearts: a brief review. 1729 29

Metallothioneins (MTs) were discovered in 1957 by Margoshes and Vallee and identified as low-molecular weight and sulphydryl rich proteins. It is not surprising that most mammalian tissues contain age related basal levels of MTs since they are involved in metalloregulatory processes that include cell growth and multiplication. In an effort to understand the biology of this intriguing tumor, various biomarkers such as oncogenes, p53 tumor suppressor gene, waf 1 protein, proliferating cell nuclear antigen, telomerase, microsatellite markers and cytogenetic changes have been examined. One biomarker which has recently shown to be expressed in various human tumors but still less reported in carcinoma is MT. Immunohistochemical detection of MT proteins in cold acetone-fixed paraffin embedded liver sections was performed by the streptavidin-avidin-biotin immuno-peroxidase complex method.
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PMID:Metallothionein: an overview. 1737 31


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