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Jeffrey N. Weitzel - One of the best experts on this subject based on the ideXlab platform.
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Tumor Protein P53 (TP53) Testing and Li-Fraumeni Syndrome
Molecular Diagnosis & Therapy, 2013Co-Authors: April D. Sorrell, Carin R. Espenschied, Julie O. Culver, Jeffrey N. WeitzelAbstract:Prevalent as an acquired abnormality in cancer, the role of tumor Protein P53 ( TP53 ) as a germline mutation continues to evolve. The clinical impact of a germline TP53 mutation is often dramatic and affects the full life course, with a propensity to develop rare tumors in childhood and multiple common cancers of unexpectedly early onset in adulthood. In this article, we review the clinical relevance of germline mutations in the TP53 tumor suppressor gene to current healthcare practice, including the optimal ways to identify patients with Li-Fraumeni syndrome (LFS), to recognize the core cancers associated with LFS, and to develop strategies for early detection of LFS-associated tumors. Several TP53 -targeted approaches to improve outcomes in LFS patients are also reviewed. A case report is used to highlight special TP53 testing dilemmas and unique challenges associated with genetic testing decisions in the current age of rapidly advancing genomic technologies.
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Tumor Protein P53 (TP53) testing and Li-Fraumeni syndrome : current status of clinical applications and future directions.
Molecular diagnosis & therapy, 2013Co-Authors: April D. Sorrell, Carin R. Espenschied, Julie O. Culver, Jeffrey N. WeitzelAbstract:Prevalent as an acquired abnormality in cancer, the role of tumor Protein P53 (TP53) as a germline mutation continues to evolve. The clinical impact of a germline TP53 mutation is often dramatic and affects the full life course, with a propensity to develop rare tumors in childhood and multiple common cancers of unexpectedly early onset in adulthood. In this article, we review the clinical relevance of germline mutations in the TP53 tumor suppressor gene to current healthcare practice, including the optimal ways to identify patients with Li-Fraumeni syndrome (LFS), to recognize the core cancers associated with LFS, and to develop strategies for early detection of LFS-associated tumors. Several TP53-targeted approaches to improve outcomes in LFS patients are also reviewed. A case report is used to highlight special TP53 testing dilemmas and unique challenges associated with genetic testing decisions in the current age of rapidly advancing genomic technologies.
Kazuyasu Sakaguchi - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of tumor suppressor Protein P53-dependent transcription by a tetramerization domain peptide via hetero-oligomerization.
Bioorganic & medicinal chemistry letters, 2012Co-Authors: Junya Wada, Rui Kamada, Toshiaki Imagawa, Yoshiro Chuman, Kazuyasu SakaguchiAbstract:Tumor suppressor Protein P53 induces cell cycle arrest, apoptosis, and senescence in response to cellular stresses. The P53 tetramer formation is essential for its functions. Despite of these crucial functions of P53 for integrity of genome, activation of the P53 signal pathway causes low induced pluripotent stem (iPS) cell generation efficiency. In this study, we report transient inhibition of P53-dependent transcription using a P53 tetramerization domain peptide that contains cell penetrating and nuclear localization signals. The peptide was efficiently introduced into cells and inhibited p21 expression via hetero-tetramerization with endogenous P53 Protein. This method can be applied towards safe and efficient iPS cell generation.
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Phosphorylation of Serine 392 Stabilizes the Tetramer Formation of Tumor Suppressor Protein P53
Biochemistry, 1997Co-Authors: Kazuyasu Sakaguchi, Hiroshi Sakamoto, John W. Erickson, Marc S. Lewis, Carl W. Anderson, Ettore Appella, Dong XieAbstract:Tumor suppressor Protein P53 is a tetrameric phosphoProtein that activates transcription from several cell cycle regulating genes in response to DNA damage. Tetramer formation is critical to P53's ability to activate transcription; however, posttranslational modifications and Protein stabilization also contribute to P53's ability to activate transcription. To determine if phosphorylation affects tetramer formation, we synthesized phosphopeptides corresponding to residues 303−393 of human P53, which includes the domain responsible for tetramer formation. Phosphate was chemically incorporated at Ser315, Ser378, or Ser392 and also at both Ser315 and Ser392. Equilibrium ultracentrifugal analyses showed that phosphorylation at Ser392 increased the association constant for reversible tetramer formation nearly 10-fold. Phosphorylation of either Ser315 or Ser378 had little effect on tetramer formation, but phosphorylation of Ser315 largely reversed the effect of phosphorylation at Ser392. Analyses by calorimetry ...
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EFFECT OF PHOSPHORYLATION ON TETRAMERIZATION OF THE TUMOR SUPPRESSOR Protein P53
Journal of protein chemistry, 1997Co-Authors: Kazuyasu Sakaguchi, Hiroshi Sakamoto, Dong Xie, John W. Erickson, Marc S. Lewis, Carl W. Anderson, Ettore AppellaAbstract:Human tumor suppressor Protein P53 is a 393-amino acid phosphoProtein that enhances transcription in response to DNA damage from several genes that regulate cell cycle progression. The tetrameric state of P53 is critical to wild-type function; the P53 tetramerization element is located in the C-terminal region of the Protein. This region is phosphorylated at several evolutionarily conserved serines, suggesting that phosphorylation may be an important regulator of P53 function. In order to determine the effect of phosphorylation on tetramer formation, we synthesized phosphopeptides corresponding to P53(Ser303–Asp393) with phosphate incorporated at Ser315, Ser378, or Ser392, and at both Ser315 and Ser392. Equilibrium ultracentrifugation analysis showed that phosphorylation at Ser392 increased the association constant for tetramer formation nearly ten-fold. By itself, phosphorylation at Ser315 or Ser378 had little effect on tetramer formation, but Ser315 largely reversed the effect of phosphorylation at Ser392. Analysis by calorimetry suggests that phosphorylation may influence subunit affinity by an enthalpy driven process.
Gerhard Brandner - One of the best experts on this subject based on the ideXlab platform.
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Influenza A virus infection of mice induces nuclear accumulation of the tumorsuppressor Protein P53 in the lung.
Archives of virology, 2001Co-Authors: Katja Technau-ihling, Christian Ihling, J. Kromeier, Gerhard BrandnerAbstract:To investigate whether the tumor suppressor P53 Protein, an indicator of DNA damage and cell stress, accumulates in the course of influenza-virus-induced murine pneumonia at the site of inflammation, female BALB/c mice were infected each with 5 × 104 infectious units of influenza virus A, strain Puerto Rico (PR) 8, by instillation into the nose and the pharynx. Two days later the mice became sick. Three and 6 days after infection the lungs of sacrificed infected and uninfected mice were examined. We assessed the presence and localisation of inflammation, the expression of influenza viral and P53 Protein, as well as of the WAF1/Cip1/SDI gene product p21. Further, the appearance of nitrotyrosine, as an indicator of the formation of peroxynitrite, and eventually of apoptotic cells was examined. No significant nuclear P53 accumulation was found in influenza virus-infected murine cells in vitro. The results show, that in the course of influenza A virus-mediated murine pneumonia inflammatory bystander cells may cause activation of the tumor suppressor Protein P53, due to oxidative stress and DNA damage, with ensuing P53-dependent upregulation of p21. Apoptosis is then mainly due to these indirect processes, with possible involvement of P53.
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Filtered, tar-free and aerosol-free cigarette-smoke causes accumulation of the tumor-suppressor Protein P53 in rodent cells.
International journal of oncology, 1994Co-Authors: A. Schulze-lutum, J Siegel, Rj Schmidt, B. Plaumann, C. Braun, C. Haessler, Gerhard Brandner, Rd HessAbstract:Cigarette smoke was filtered with a Cambridge glass fiber filter retaining 99.9% of the tar and aerosol fraction and diluted 1:5 with air. The murine cell line L929 was exposed to this smoke preparation for periods of up to 10 min. Thereafter the following parameters were determined at different times: Nuclear accumulation of the tumor suppressor Protein P53 indicating chromatin injury (by immunostaining); apoptotic DNA fragmentation (by DNA end labelling with biotin-16-dUTP in the presence of terminal deoxyribonucleotidyl transferase); the intracellular level of reactive oxygen intermediates (ROI) (by cytofluorimetry with the fluorigenic stain 2',7'-dichlorofluorescin diacetate). After 1 min exposure to 1:5 air-diluted filtered cigarette smoke maximal P53 accumulation occured about 20 h later, whereas maximal DNA fragmentation and apoptosis and maximal ROI levels were found after 10 min of exposure. Obviously, even the diluted, tar- and aerosol-free fraction of cigarette smoke has the potency, after 1 min of exposure only, to exert severe DNA damage, a potential transformation risk for the surviving cell fraction, in murine cell cultures as indicated by stabilization and accumulation of the tumor suppressor Protein P53.
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induction of nuclear accumulation of the tumor suppressor Protein P53 by dna damaging agents
Oncogene, 1993Co-Authors: M Fritsche, C. Haessler, Gerhard BrandnerAbstract:Cancer therapy drugs, such as diamminedichloroplatinum (cisplatin), mitomycin C, etoposide and a number of other compounds, as well as energy-rich radiation, are known to act on cellular DNA. These agents are shown to induce nuclear accumulation of the so-called tumor-suppressor Protein P53 in fibroblastoid cells, as well as in epithelioid normal and immortalized cells of murine, simian, and human origin. P53 accumulation starts a few hours after treatment and can remain detectable in surviving cells for at least 20 days. Accumulation occurs because of increased P53 Protein stability and depends on ongoing translation. It is not the result of enhanced gene expression. A number of cell cycle inhibitors do not affect P53 Protein accumulation, suggesting that the process may start from several points in the cell cycle. Since the increase in the nuclear P53 Protein levels occurs within a few hours in most of the treated normal diploid cells, it is unlikely that the accumulated P53 Protein is derived from a mutated P53 gene. The results obtained are in accordance with the view that the DNA damage-induced P53 accumulation may either inhibit cell growth, allowing DNA repair processes, or, in the case of severe damage, initiate apoptosis.
April D. Sorrell - One of the best experts on this subject based on the ideXlab platform.
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Tumor Protein P53 (TP53) Testing and Li-Fraumeni Syndrome
Molecular Diagnosis & Therapy, 2013Co-Authors: April D. Sorrell, Carin R. Espenschied, Julie O. Culver, Jeffrey N. WeitzelAbstract:Prevalent as an acquired abnormality in cancer, the role of tumor Protein P53 ( TP53 ) as a germline mutation continues to evolve. The clinical impact of a germline TP53 mutation is often dramatic and affects the full life course, with a propensity to develop rare tumors in childhood and multiple common cancers of unexpectedly early onset in adulthood. In this article, we review the clinical relevance of germline mutations in the TP53 tumor suppressor gene to current healthcare practice, including the optimal ways to identify patients with Li-Fraumeni syndrome (LFS), to recognize the core cancers associated with LFS, and to develop strategies for early detection of LFS-associated tumors. Several TP53 -targeted approaches to improve outcomes in LFS patients are also reviewed. A case report is used to highlight special TP53 testing dilemmas and unique challenges associated with genetic testing decisions in the current age of rapidly advancing genomic technologies.
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Tumor Protein P53 (TP53) testing and Li-Fraumeni syndrome : current status of clinical applications and future directions.
Molecular diagnosis & therapy, 2013Co-Authors: April D. Sorrell, Carin R. Espenschied, Julie O. Culver, Jeffrey N. WeitzelAbstract:Prevalent as an acquired abnormality in cancer, the role of tumor Protein P53 (TP53) as a germline mutation continues to evolve. The clinical impact of a germline TP53 mutation is often dramatic and affects the full life course, with a propensity to develop rare tumors in childhood and multiple common cancers of unexpectedly early onset in adulthood. In this article, we review the clinical relevance of germline mutations in the TP53 tumor suppressor gene to current healthcare practice, including the optimal ways to identify patients with Li-Fraumeni syndrome (LFS), to recognize the core cancers associated with LFS, and to develop strategies for early detection of LFS-associated tumors. Several TP53-targeted approaches to improve outcomes in LFS patients are also reviewed. A case report is used to highlight special TP53 testing dilemmas and unique challenges associated with genetic testing decisions in the current age of rapidly advancing genomic technologies.
Cathy W. Levenson - One of the best experts on this subject based on the ideXlab platform.
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Copper alters the conformation and transcriptional activity of the tumor suppressor Protein P53 in human Hep G2 cells.
Experimental biology and medicine (Maywood N.J.), 2005Co-Authors: Nadine M. Tassabehji, Jacob W. Vanlandingham, Cathy W. LevensonAbstract:The tumor suppressor Protein P53 plays a role in the molecular response to DNA damage by acting as a DNA-binding transcription factor that regulates specific target genes to arrest the cell cycle, induce repair mechanisms, and initiate apoptotic cell death. To test the effect of copper on the transcriptional activity of P53, Hep G2 cells were transiently transfected with a luciferase reporter gene downstream from multiple P53 response elements. Co-transfection with the P53 gene resulted in a 6-fold increase in luciferase activity, showing that P53 acts as a transcription factor in this system. However, in the presence of copper, luciferase activity was significantly reduced. Oligonucleotide arrays representing 145 known P53-associated genes were hybridized with biotinylated cDNAs from mRNA extracted from control and copper-treated Hep G2 cells. Among the genes that were differentially regulated were fos, RB1, glutathione peroxidase, TGF-β, and 15-lipoxygenase, a gene known to be activated by mutant P53. A...
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Zinc inhibits the nuclear translocation of the tumor suppressor Protein P53 and protects cultured human neurons from copper-induced neurotoxicity
NeuroMolecular Medicine, 2002Co-Authors: Jacob W. Vanlandingham, Cheryl A Fitch, Cathy W. LevensonAbstract:High concentrations of the trace metal zinc (Zn) have previously been shown to provide transient protection of cells from apoptotic death. The molecular mechanisms responsible for this protection are not known. Thus, this work explored the ability of Zn to protect human neurons in culture (NT2-N) from Cu-mediated death and tested the hypotheses that the tumor-suppressor Protein P53 plays a role in Cu-induced neuronal death and is part of the mechanism of Zn protection. Copper toxicity (100 µ M ) resulted in significant apoptotic neuronal death by 12 h. Addition of 100 µ M Zn to Cu-treated cells increased neuronal death. However, the addition of 700 µ M Zn to Cu-treated cells resulted in neuronal viability that was not different from untreated controls through 24 h. P53 mRNA abundance, while increased by the addition of Cu and 100 µ M Zn, was decreased to 50% of control with the addition of 500 µ M Zn in Cu-treated cells, and to 10% of control with 700 µ M Zn. Consistent with its role as a transcription factor, both Western analysis and immunocytochemistry showed significant increases in nuclear P53 Protein levels in Cu toxicity. The role of P53 in Cu-mediated apoptosis was further confirmed by elimination of apoptosis in Cu-treated cells that had been transfected with a dominant-negative P53 construct to prevent P53 expression. Furthermore, the addition of 500–700 µ M Zn prevented the movement of P53 into the nucleus suggesting that Zn not only protects neurons from Cu toxicity by regulating P53 mRNA abundance but also by preventing the translocation of P53 to the nucleus.
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tumor suppressor Protein P53 mrna and subcellular localization are altered by changes in cellular copper in human hep g2 cells
Journal of Nutrition, 2001Co-Authors: Vijaya S Narayanan, Cheryl A Fitch, Cathy W. LevensonAbstract:Copper toxicity causes hepatic damage that can lead to the development of hepatocarcinoma. Similarly, copper deficiency has been reported to increase hepatocyte tumorigenesis. Thus, the objective of this work was to explore the role of copper toxicity and deficiency in the regulation of the tumor suppressor Protein P53. Using Northern analysis, Western analysis, immunocytochemistry and the human hepatoma cell line Hep G2, this work showed that elevations in hepatocyte copper consistent with Wilson's disease (5.7-fold increase) induced P53 mRNA and confirmed that copper toxicity is correlated with apoptotic cell death. However, Western analysis and immunocytochemistry showed that post-transcriptional mechanisms are a significant part of the process, with P53 translocation from the cytosol into the nucleus of copper-treated cells. Treatment of Hep G2 cells with increasing concentrations of the copper chelator tetraethylenepentamine (TEPA, 0-50 μmol/L, 48 h) reduced cellular copper and increased mean P53 mRNA abundance by over fourfold with nuclear translocation of the wild-type Protein. However, TEPA treatment did not result in a loss of cell viability or appear to induce apoptosis.
