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The P53 Family
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Book Synopsis The P53 Family by : Arnold Jay Levine
Download or read book The P53 Family written by Arnold Jay Levine and published by . This book was released on 2010 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume offers a comprehensive review of the functions of the p53 family. The contributors examine the normal roles of these transcription factors, their evolution, the regulatory mechanisms that control p53 activity, and the part played by p53 mutations in tumorigenesis.
Book Synopsis Polyploidization and Cancer by : Randy Y.C. Poon
Download or read book Polyploidization and Cancer written by Randy Y.C. Poon and published by Springer Science & Business Media. This book was released on 2011-01-11 with total page 157 pages. Available in PDF, EPUB and Kindle. Book excerpt: Limiting genome replication to once per cell cycle is vital for maintaining genome stability. Although polyploidization is of physiologically importance for several specialized cell types, inappropriate polyploidization is believed to promote aneuploidy and transformation. A growing body of evidence indicates that the surveillance mechanisms that prevent polyploidization are frequently perturbed in cancers. Progress in the past several years has unraveled some of the underlying principles that maintain genome stability. This book brings together leaders of the field to overview subjects relating to polyploidization and cancer.
Book Synopsis Elucidating the Role of P53 and the P53 Target Gene Siva in Embryonic Development and Tumorigenesis by : Jeanine Louise Frey Van-Nostrand
Download or read book Elucidating the Role of P53 and the P53 Target Gene Siva in Embryonic Development and Tumorigenesis written by Jeanine Louise Frey Van-Nostrand and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The p53 protein plays a critical role in tumor suppression, as evidenced by its high mutation rate in human tumors and the observation that p53-null mice get cancer with 100% penetrance. p53 is a stress sensor that responds to cellular assaults, such as DNA damage or serum starvation, by inducing downstream effector functions, including apoptosis and cell cycle arrest. p53 itself is a transcription factor that promotes its downstream functions through its ability to transcriptionally activate downstream targets genes, although p53 also has transactivation-independent functions. However, the role that p53 plays in development and the role its target genes play in development and tumor suppression are not well defined. First, we sought to analyze the role of p53 transcriptional activation in development. Using knock-in mice expressing a p53 transactivation domain mutant (p5325,26,53,54), which does not bind Mdm2, we found that developmental defects caused by unrestrained p53 require p53's transactivation ability, as p5325,26,53,54/- mice are viable. Surprisingly, we also found that expression of p5325,26,53,54 in the presence of wild-type p53 induces embryonic lethality and a spectrum of phenotypes characteristic of a congenital syndrome known as CHARGE, including coloboma, inner and outer ear malformations, heart outflow tract defects, and craniofacial defects. We find that p5325,26,53,54 mutant protein is able to stabilize and hyperactivate wild-type p53, driving p53 to inappropriately induce target gene expression and trigger cell-cycle arrest and apoptosis during development. We further find that p53 is activated in CHD7-mutant CHARGE syndrome patient samples and upon genetic ablation of Chd7 in mouse cells. Additionally, p53-heterozygosity is able to partially rescue Chd7 null embryonic phenotypes, indicating that Chd7 deficiency provokes p53 activation and p53-dependent phenotypes. Thus, through the use of p5325,26,53,54 mice, we have uncovered a critical role for transactivation in provoking developmental defects induced by unrestrained p53 and revealed a novel and critical role for p53 in promoting human CHARGE syndrome. Subsequently, we sought to uncover the role of the p53 family as a whole, including the two related transcription factors p63 and p73, in development. While p53 null mice are viable, p63 null mice are perinatal lethal with epidermal and limb defects and p73 null mice typically die within the first two months of life and manifest neuronal defects. To determine if the absence of more severe developmental phenotypes is due to redundancy between the p53 family members, we bred and analyzed compound knockout mice. Analysis of compound knockout embryos revealed viability of all double knockout embryos (p53p63, p53p73, and p53p63) and five allele knockout embryos (double knockout and heterozygous for the remaining gene) during embryogenesis with the only defects detected being accounted for by loss of single p53 family members. Surprisingly, we also identified a single viable triple knockout at E10.5 with normal morphology except for hypoplastic cardiac cushions. Thus, these results suggest that p53 family members are neither critical nor redundant for relatively normal development. We next sought to determine the role of the p53 target gene Siva in both development and tumorigenesis. Our lab previously identified Siva as a p53 target gene critically important for p53-dependent apoptosis. Here we generated a Siva knockout mouse strain using gene-trap technology. Analysis of homozygous Siva mutant mice, revealed mid-gestational embryonic lethality associated with both embryonic and extra-embryonic defects, including developmental delay and defects of neural tube closure, yolk sac vasculature, and chorioallantoic fusion. The defects associated with Siva deficiency resembled those in embryos with loss of key components of TGF [beta]/SMAD signaling pathways, and notably, Siva null embryos displayed reduced SMAD protein levels and aberrant SMAD target gene expression. Thus, loss of Siva results in embryonic lethality associated with defects in SMAD signaling. Due to the embryonic lethality associated with Siva loss, we went on to generate a conditional Siva knockout mouse strain for studies of Siva in tumor suppression. Using a Kras-dependent non-small cell lung cancer model, we found surprisingly that Siva is necessary for efficient tumorigenesis in this model, as Siva-deficiency results in reduced tumor number and tumor burden. Additionally, Siva knockdown in non-small cell lung cancer cell lines resulted in reduced proliferation and tumorigenic potential. Furthermore, Siva loss inhibited mTOR signaling, induced autophagy, and reduced mitochondrial respiration, suggesting that Siva is necessary for normal metabolic function to promote proliferation. Moreover, Siva levels have prognostic ability for human non-small cell lung cancer patient survival. Therefore, our findings reveal that the p53 target gene Siva enables Kras-dependent lung cancer development and is necessary for oxidative phosphorylation, and that Siva levels could be used to estimate the prognosis of non-small cell lung cancer patient survival. Collectively, these results significantly expand our knowledge of the role of p53, the p53 family, and the p53 target gene Siva in development as well as the role of Siva in tumorigenesis. We found that unrestrained p53 results in developmental defects resembling CHARGE syndrome and that compound loss of the p53 family members does not promote profound developmental phenotypes other than those observed in single mutants. Moreover, we found that Siva is necessary for both proper embryonic development and efficient non-small cell lung cancer tumor development through roles in SMAD signaling and metabolism, respectively.
Book Synopsis Evolutionary History of the P53 Family DNA-binding Domain: Insights from an Alvinella Pompejana Homolog by : Qiang Zhang
Download or read book Evolutionary History of the P53 Family DNA-binding Domain: Insights from an Alvinella Pompejana Homolog written by Qiang Zhang and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The extremophile Alvinella pompejana, an annelid worm living on the edge of hydrothermal vents in the Pacific Ocean, is an excellent model system for studying factors that govern protein stability. Low intrinsic stability is a crucial factor for the susceptibility of the transcription factor p53 to inactivating mutations in human cancer. Understanding its molecular basis may facilitate the design of novel therapeutic strategies targeting mutant p53. By analyzing expressed sequence tag (EST) data, we discovered a p53 family gene in A. pompejana. Protein crystallography and biophysical studies showed that it has a p53/p63-like DNA-binding domain (DBD) that is more thermostable than all vertebrate p53 DBDs tested so far, but not as stable as that of human p63. We also identified features associated with its increased thermostability. In addition, the A. pompejana homolog shares DNA-binding properties with human p53 family DBDs, despite its evolutionary distance, consistent with a potential role in maintaining genome integrity. Through extensive structural and phylogenetic analyses, we could further trace key evolutionary events that shaped the structure, stability, and function of the p53 family DBD over time, leading to a potent but vulnerable tumor suppressor in humans.
Download or read book P53 written by Sue Armstrong and published by . This book was released on 2014-11-20 with total page 288 pages. Available in PDF, EPUB and Kindle. Book excerpt: All of us have lurking in our DNA a most remarkable gene, which has a crucial job - it protects us from cancer. Known simply as p53, this gene constantly scans our cells to ensure that they grow and divide without mishap, as part of the routine maintenance of our bodies. If a cell makes a mistake in copying its DNA during the process of division, p53 stops it in its tracks, summoning a repair team before allowing the cell to carry on dividing. If the mistake is irreparable and the rogue cell threatens to grow out of control, p53 commands the cell to commit suicide. Cancer cannot develop unless p53 itself is damaged or prevented from functioning normally. Perhaps unsurprisingly, p53 is the most studied single gene in history. This book tells the story of medical science's mission to unravel the mysteries of this crucial gene, and to get to the heart of what happens in our cells when they turn cancerous. Through the personal accounts of key researchers, p53: The Gene that Cracked the Cancer Code reveals the fascination of the quest for scientific understanding, as well as the huge excitement of the chase for new cures - the hype, the enthusiasm, the lost opportunities, the blind alleys, and the thrilling breakthroughs. And as the long-anticipated revolution in cancer treatment tailored to each individual patient's symptoms begins to take off at last, p53 remains at the cutting edge. This timely tale of scientific discovery highlights the tremendous recent advances made in our understanding of cancer, a disease that affects more than one in three of us at some point in our lives.
Book Synopsis Non-coding RNAs and Cancer by : Muller Fabbri
Download or read book Non-coding RNAs and Cancer written by Muller Fabbri and published by Springer Science & Business Media. This book was released on 2013-10-28 with total page 287 pages. Available in PDF, EPUB and Kindle. Book excerpt: The discovery of microRNAs and its role as gene expression regulators in human carcinogenesis represents one of the most important scientific achievements of the last decade. More recently, other non-coding RNAs have been discovered and its implications in cancer are emerging as well, suggesting a broader than anticipated involvement of the non-coding genome in cancer. Moreover, completely new and unexpected functions for microRNAs are being revealed, leading to the identification of new anticancer molecular targets. This book represents a comprehensive guide on non-coding RNAs and cancer, spanning from its role as cancer biomarkers, to providing the most useful bioinformatic tools, to presenting some of the most relevant discoveries, which indicates how these fascinating molecules act as fine orchestrators of cancer biology.
Book Synopsis The Hippo Signaling Pathway and Cancer by : Moshe Oren
Download or read book The Hippo Signaling Pathway and Cancer written by Moshe Oren and published by Springer Science & Business Media. This book was released on 2013-03-19 with total page 345 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Hippo signaling pathway is rapidly gaining recognition as an important player in organ size control and tumorigenesis, and many leading scientists are showing increased interest in this growing field and it's relation to cancer. The chapters in this volume cover virtually all aspects of tumor biology, because members of the Hippo Pathway have been associated with numerous well-established cell signaling pathways, just to name a few; Ras, Wnt, TGFbeta and p53. Moreover, Hippo signaling is not solely involved in regulating “classic” tumor characteristics such as cell proliferation, survival and growth, but is also diversely involved in cell-autonomous and non-cell-autonomous differentiation, migration and organ size control. The primary audience are researchers interested in basic science in the areas of tumor suppression, cell cycle and size regulation, development and differentiation.
Book Synopsis The Role of the P53 Family Proteins in Hydroxyurea Induced Embryotoxicity in the Organogenesis Stage Mouse Embryo by : Nazem El Husseini
Download or read book The Role of the P53 Family Proteins in Hydroxyurea Induced Embryotoxicity in the Organogenesis Stage Mouse Embryo written by Nazem El Husseini and published by . This book was released on 2018 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "The embryonic stress response to DNA damage during organogenesis was examined using the model teratogen, hydroxyurea. Intraperitoneal administration of hydroxyurea (400 mg/kg or 600 mg/kg) to timed pregnant CD-1 mice on gestational day 9 significantly affected the expression of ~1300 transcripts in the embryo within three hours. Pathway analysis predicted that the P53 signaling pathway was the most activated in response to hydroxyurea. The steady-state levels of P53 and its phosphorylation increased dramatically in hydroxyurea-exposed embryos. The nuclear localization of phosphorylated P53 was increased significantly in the embryo heart and rostral and caudal neuroepithelia. Hydroxyurea also induced P53 transcriptional activity, leading to the upregulation of P53 downstream targets involved in DNA damage repair, cell cycle arrest and apoptosis. Using a Trp53 null transgenic mouse model, the effects of treatment with hydroxyurea on P53 family members, P63 and P73, were determined in the gestational day 9 embryo. Appreciable amounts of P63 and P73 were detected under normal conditions; hydroxyurea did not affect their steady-state or phosphorylation levels. Trp63 and Trp73 transcript levels were affected by hydroxyurea treatment, although only Trp73 levels were P53-dependent. As transcription factors, neither P63 nor P73 were capable of compensating for the absence of P53 in upregulating the expression of downstream targets involved in cell cycle arrest (Cdkn1a, Rb1) or apoptosis (Fas, Pmaip1) in response to hydroxyurea exposure. Hydroxyurea induction of Caspase-3 and MST-1 cleavage, markers for apoptosis and DNA damage repair, required the presence of P53. Thus, P53 is the main member of the P53 family that responds to genotoxic stress in the organogenesis-stage embryo.To determine whether P53 acts as a suppressor or inducer of hydroxyurea embryotoxicity, Trp53+/+, Trp53+/- and Trp53-/- embryos were exposed in utero on gestational day 9 with saline or hydroxyurea (200 or 400 mg/kg). On gestational day 18, Trp53-/- fetuses from the saline treatment group were found to exhibit a higher rate of malformations compared to their Trp53+/+ littermates. Hydroxyurea treatment induced a dose-dependent increase in resorptions and congenital malformations; these included hypoplastic tails and fore- and hind-limb syndactly, oligodactyly and amelia. In the 200 mg/kg treatment group, hydroxyurea exposed fetuses lacking P53 had a higher rate of malformations than their Trp53+/+ littermates and the rate of resorptions was elevated in these fetuses after exposure to 400 mg/kg hydroxyurea. Thus, the organogenesis stage embryo responds to hydroxyurea-induced stress by activating the P53 signaling pathway that mediates DNA damage repair, cell cycle arrest and apoptotic factors to suppress hydroxyurea embryotoxicity. " --
Book Synopsis A Role for the P53 Family in Regulating Epigenetically Controlled Genes by : Kristy Marie Powers
Download or read book A Role for the P53 Family in Regulating Epigenetically Controlled Genes written by Kristy Marie Powers and published by . This book was released on 2007 with total page 106 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Targeting [Delta]N-isoforms of the P53 Family for Cancer Therapy by : Anne Catherine Bretz
Download or read book Targeting [Delta]N-isoforms of the P53 Family for Cancer Therapy written by Anne Catherine Bretz and published by . This book was released on 2014 with total page 236 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis The Philadelphia Chromosome: A Genetic Mystery, a Lethal Cancer, and the Improbable Invention of a Lifesaving Treatment by : Jessica Wapner
Download or read book The Philadelphia Chromosome: A Genetic Mystery, a Lethal Cancer, and the Improbable Invention of a Lifesaving Treatment written by Jessica Wapner and published by The Experiment, LLC. This book was released on 2014-04-08 with total page 345 pages. Available in PDF, EPUB and Kindle. Book excerpt: One of The Wall Street Journal’s 10 Best Nonfiction Books of the Year Philadelphia, 1959: A scientist scrutinizing a single human cell under a microscope detects a missing piece of DNA. That scientist, David Hungerford, had no way of knowing that he had stumbled upon the starting point of modern cancer research— the Philadelphia chromosome. It would take doctors and researchers around the world more than three decades to unravel the implications of this landmark discovery. In 1990, the Philadelphia chromosome was recognized as the sole cause of a deadly blood cancer, chronic myeloid leukemia, or CML. Cancer research would never be the same. Science journalist Jessica Wapner reconstructs more than forty years of crucial breakthroughs, clearly explains the science behind them, and pays tribute—with extensive original reporting, including more than thirty-five interviews—to the dozens of researchers, doctors, and patients with a direct role in this inspirational story. Their curiosity and determination would ultimately lead to a lifesaving treatment unlike anything before it. The Philadelphia Chromosome chronicles the remarkable change of fortune for the more than 70,000 people worldwide who are diagnosed with CML each year. It is a celebration of a rare triumph in the battle against cancer and a blueprint for future research, as doctors and scientists race to uncover and treat the genetic roots of a wide range of cancers.
Book Synopsis Clinical Gynecology by : Eric J. Bieber
Download or read book Clinical Gynecology written by Eric J. Bieber and published by Cambridge University Press. This book was released on 2015-04-23 with total page 1127 pages. Available in PDF, EPUB and Kindle. Book excerpt: Written with the busy practice in mind, this book delivers clinically focused, evidence-based gynecology guidance in a quick-reference format. It explores etiology, screening, tests, diagnosis, and treatment for a full range of gynecologic health issues. The coverage includes the full range of gynecologic malignancies, reproductive endocrinology and infertility, infectious diseases, urogynecologic problems, gynecologic concerns in children and adolescents, and surgical interventions including minimally invasive surgical procedures. Information is easy to find and absorb owing to the extensive use of full-color diagrams, algorithms, and illustrations. The new edition has been expanded to include aspects of gynecology important in international and resource-poor settings.
Book Synopsis The Growing Complexity of the P53-family and Their Target Genes by : Max Koeppel
Download or read book The Growing Complexity of the P53-family and Their Target Genes written by Max Koeppel and published by . This book was released on 2011 with total page 197 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Molecular Biology of The Cell by : Bruce Alberts
Download or read book Molecular Biology of The Cell written by Bruce Alberts and published by . This book was released on 2002 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis From Sea Anemone to Homo Sapiens by :
Download or read book From Sea Anemone to Homo Sapiens written by and published by . This book was released on 2009 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The human genome contains three transcription factors termed p53, p63 and p73 which are related orthologues. The function of the p53 protein is to respond to a wide variety of stresses which can disrupt the fidelity of DNA replication and cell division in somatic cells of the body. These stress signals, such as DNA damage, increase the mutation rate during DNA duplication and so an active p53 protein responds by eliminating clones of cells with mutations employing apoptosis, senescence or cell cycle arrest. In this way the p53 protein acts as a tumor suppressor preventing the mutations that can lead to cancers. The p63 and p73 proteins act in a similar fashion to protect the germ line cells in females (eggs). In addition the p63 protein plays a central role in the formation of epithelial cell layers and p73 plays a critical role in the formation of several structures in the central nervous system. Based upon their amino acid sequences and structural considerations the oldest organisms that contain an ancestor of the p53/p63/p73 gene are the sea anemone or hydra. The present day representatives of these animals contain a p63/p73 like ancestor gene and the protein functions in germ cells of this animal to enforce the fidelity of DNA replication after exposure to ultraviolet light. Thus the structure and functions of this gene family have been preserved for over one billion years of evolution. Other invertebrates such as the worm, the fly and the clam contain a very similar ancestor gene with a similar set of functions. The withdrawal of a food source from a worm results in the p63/p73 mediated apoptosis of the eggs so that new organisms will not be hatched into a poor environment. A similar response is thought to occur in humans. Thus this ancestor gene ensures the fidelity of the next generation of organisms. The first time a clearly distinct new p53 gene arises is in the cartilaginous fish and in the bony fish a separation of the p.
Book Synopsis Targeting Delta-isoforms of the P53 Family for Cancer Therapy by : Anne Catherine Bretz
Download or read book Targeting Delta-isoforms of the P53 Family for Cancer Therapy written by Anne Catherine Bretz and published by . This book was released on 2014 with total page 236 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Author :United States. Public Health Service. Office of the Surgeon General Publisher : ISBN 13 : Total Pages :728 pages Book Rating :4.:/5 (318 download)
Book Synopsis How Tobacco Smoke Causes Disease by : United States. Public Health Service. Office of the Surgeon General
Download or read book How Tobacco Smoke Causes Disease written by United States. Public Health Service. Office of the Surgeon General and published by . This book was released on 2010 with total page 728 pages. Available in PDF, EPUB and Kindle. Book excerpt: This report considers the biological and behavioral mechanisms that may underlie the pathogenicity of tobacco smoke. Many Surgeon General's reports have considered research findings on mechanisms in assessing the biological plausibility of associations observed in epidemiologic studies. Mechanisms of disease are important because they may provide plausibility, which is one of the guideline criteria for assessing evidence on causation. This report specifically reviews the evidence on the potential mechanisms by which smoking causes diseases and considers whether a mechanism is likely to be operative in the production of human disease by tobacco smoke. This evidence is relevant to understanding how smoking causes disease, to identifying those who may be particularly susceptible, and to assessing the potential risks of tobacco products.
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