Functional Significance of Mutant P53 in Breast Cancer PDF Download
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Author: Kristen Lynn Murphy
Publisher:
ISBN:
Category :
Languages : en
Pages : 446
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Book Description
Author: Kristen Lynn Murphy
Publisher:
ISBN:
Category :
Languages : en
Pages : 446
Get Book Here
Book Description
Author: Kristen Lynn Murphy
Publisher:
ISBN:
Category :
Languages : en
Pages : 446
Get Book Here
Book Description
Approximately 40% of breast cancer patients have tumors containing alterations in the p53 tumor suppressor gene; these patients are known to have a poorer prognosis than those lacking p53 mutations. Arg-His (R-H) mutations are frequently observed at amino acid 175 of p53 (equivalent to murine 172) in such tumors. Expression of a mammary-targeted p53 172R-H transgene rarely induces spontaneous tumors in mice, but carcinogen-treated p53 172R-H transgenic mice develop tumors much earlier than controls. Furthermore, expression of this transgene predisposes tumors induced by carcinogen treatment or oncogene coexpression to the development of aneuploidy. The objective of this proposal is to examine the mechanism by which this particular p53 mutant promotes aneuploidy and tumorigenesis. This will be accomplished through both analysis of gene transcription and analysis of the mitotic machinery and cellular apoptosis. Recent in vitro studies indicate that expression of the p53 17 SR-H mutant in mammary epithelial cells may promote mammary tumorigenesis by deregulating centrosome replication and reducing both basal and DNA-damage-induced apoptosis. Transcriptional regulation studies are currently in progress to identify possible novel protein-protein interactions between the mutant and other proteins leading to the up- or down-regulation of genes linked to the promotion of genomic instability and cancer.
Author: Ygal Haupt
Publisher: Frontiers Media SA
ISBN: 2889199614
Category : Medicine (General)
Languages : en
Pages : 99
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Book Description
TP53 gene mutations are present in more than half of all human cancers. The resulting proteins are mostly full-length with a single amino acid change and are abundantly expressed in cancer cells. Some of the mutant p53 proteins gain oncogenic functions (GOF) through which it actively contribute to the aberrant cell proliferation, increased resistance to apoptotic stimuli and ability to metastasize. Gain of function mutant p53 proteins can transcriptionally regulate the expression of a large plethora of target genes. This mainly occurs through the formation of oncogenic transcriptional competent complexes that include mutant p53 protein, known transcription factors, posttranslational modifiers and scaffold proteins. Mutant p53 protein can also transcriptionally regulate the expression of microRNAs, small non-coding RNAs that regulate gene expression at the posttranscriptional level. Each microRNA can putatively target the expression of hundred mRNAs and consequently impact on many cellular functions. Thus, gain of function mutant p53 proteins can exert their oncogenic activities through the modulation of both non-coding and coding regions of human genome. Over the past 3 decades, the regulation of p53 has been extensively studied. However, the regulation of mutant p53 remained largely unexplored. This snapshot focuses on recent discovery of mutant p53 GOF and regulation.
Author: Gerard P. Zambetti
Publisher: Springer Science & Business Media
ISBN: 0387301275
Category : Medical
Languages : en
Pages : 246
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Book Description
The current year (2004) marks the Silver Anniversary of the discovery of the p53 tumor suppressor. The emerging ?eld ?rst considered p53 as a viral antigen and then as an oncogene that cooperates with activated ras in transforming primary cells in culture. Fueling the concept of p53 acting as a transforming factor, p53 expression was markedly elevated in various transformed and tumorigenic cell lines when compared to normal cells. In a simple twist of fate, most of the studies conducted in those early years inadvertently relied on a point mutant of p53 that had been cloned from a normal mouse genomic library. A bona ?de wild-type p53 cDNA was subsequently isolated, ironically, from a mouse teratocarcinoma cell line. A decade after its discovery, p53 was shown to be a tumor suppressor that protects against cancer. It is now recognized that approximately half of all human tumors arise due to mutations within the p53 gene. As remarkable as this number may seem, it signi?cantly underrepresents how often the p53 pathway is targeted during tumorigenesis. It is my personal view, as well as many in the p53 ?eld, that the p53-signaling pathway is corrupted in nearly 100% of tumors. If you are interested in understanding cancer and how it develops, you must begin by studying p53 and its pathway. After demonstrating that p53 functions as a tumor suppressor the ?eld exploded and p53 became a major focus of scientists around the world.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 55
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Book Description
Mutation of the p53 gene is very frequent in breast cancer. In normal cells induction of wild-type p53 function leads to either cell cycle arrest or cell death. Loss of this function can contribute to oncogenic cell transformation. Additionally the presence of mutant forms of p53 in breast tumor cells may actually facilitate the process of tumorigenesis. The properties of mutant p53 proteins in vitro and in breast tumor cell lines will be studied, experiments will focus on analysis of the structure and modification of mutant p53 proteins as well as the effect of cellular signalling on p53 function. Additionally it is planned to establish breast cell lines expressing inducible mutant p53 to determine the effect of such mutants on parameters of cell cycle, growth and death. We have discovered that all mutant forms of p53 tested are capable of binding specifically to p53 response elements present in pS3 target genes at lower but not at physiological temperatures. Furthermore, we have identified a means by which such binding is stabilized at the higher temperature. This will allow us to explore means to develop molecules that might have the outcome of converting p53 in breast tumor cells from mutant to wild-type in function. One approach will be to develop a yeast-based screen for mutant p53 modifying genes. Such reagents would have clear therapeutic advantages.
Author: Damian Jerome Junk
Publisher:
ISBN:
Category :
Languages : en
Pages : 372
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Book Description
Breast cancer is the most frequently diagnosed form of cancer in women and the second leading cause of cancer-related deaths. Breast cancer is a heterogeneous disease consisting of many types of tissue neoplasia, and there appears to be no model of how a particular lesion develops into an aggressive, malignant, invasive carcinoma. Genetic mutation and aberrant epigenetic regulation are among the most common events that lead to neoplasia. In breast cancer, p53 mutation is the most common genetic defect related to a single gene. Therefore, this dissertation focuses on the mechanisms and consequences of p53 mutation during breast tumorigenesis. Genome-wide analysis of gene expression and epigenetic modifications in a panel of breast cancer cell lines suggested that p53 mutation and aberrant epigenetic silencing were cooperating mechanisms in the silencing of wild-type p53 target genes during cancer progression. Therefore, models of p53 inactivation were created in non-malignant human mammary epithelial cells to determine the role of p53 mutation on the epigenetic status of its target genes and the acquisition of malignant phenotypes. Comparisons of each model demonstrated that differing modes of p53 inactivation produced different functional consequences. Loss of wild-type p53 function alone ablated the normal cellular response to external stress stimuli, but had no affect on the expressionof genes or epigenetic status in untreated cells. Introduction of missense mutant p53 protein caused very few changes when the protein was expressed at low levels. However, accumulation of mutant p53 caused a variety of gene expression changes and interfered with endogenous wild-type p53. The accumulation of mutant p53 also caused an increase in migration and invasion of the cells that expressed it. Interestingly, epigenetic aberrations were not detected in response to any of the p53 manipulations. These data suggest that accumulation of missense mutation is particularly dangerous to normal cells. They also suggest that p53 mutation and epigenetic aberration are two distinct mechanisms, which overlap and cooperate during tumorigenesis. These data suggest that treatment strategies for human breast cancer should include modalities to target both defects for increased efficacy.
Author: Mumtaz Anwar
Publisher: BoD – Books on Demand
ISBN: 1839681454
Category : Science
Languages : en
Pages : 136
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Book Description
p53 is a protein that plays an important role in the regulation of cell division and thereby offers protection to the cell against malignant transformation. This is the most well-studied and most appreciated role of p53, due to which the protein is famously known as the “guardian of the genome.” It is the most studied protein in all forms of cancer research, with much of this research investigating p53’s role in tumor suppression. However, research has also shown that p53 plays a role in a wide range of other cellular functions, like serving as a biomarker for environmental pollution. Even as a tumor suppressor and transcription factor, many aspects of p53 function are still obscure, and research in the field is continually attempting to shed light on these functions. This book examines and discusses the myriad roles of p53 and different aspects of its functions. Chapters examine p53 in cancer prevention, DNA repair, gene regulation, and more.
Author: Swati Palit Deb
Publisher: Springer
ISBN: 9401792119
Category : Medical
Languages : en
Pages : 376
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Book Description
This book provides the readers with an overview of research on p53, which has been shown to play a role in numerous crucial biological pathways in normal and cancer cells. Leading scientist in the field, who have all made direct contributions to the understanding of the molecular events underpinning p53 function, have been invited to contribute the various chapters, which discuss the current knowledge of the signaling cascades that are activated by mutations in p53 and overexpression of MDM2, frequently found in human cancer and are major causes of oncogenesis. This book features chapters on the molecular basis of oncogenesis induced by gain of function mutation of p53, signaling pathways induced by MDM2 overexpression, control of mutant or wild-type p53 function by MDM2 and MDMX, p53 mutation in hereditary cancer and structural aspects that activate mutant p53 which can be targeted by drug therapy. This book should be useful for scientists at all levels.
Author: Alexander Bürkle
Publisher: Springer Science & Business Media
ISBN: 0387360050
Category : Medical
Languages : en
Pages : 260
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Book Description
This is the most comprehensive, up-to-date reference on this post-translational modification of proteins, which is intimately linked with DNA repair, maintenance of genomic stability, transcriptional regulation, cell death and a variety of other cellular phenomena as well as with a variety of pathophysiological conditions, including ischemia-reperfusion damage, Parkinson’s disease, Type I diabetes mellitus, hemorrhagic and septic shock and other inflammatory conditions. Richly illustrated, it offers 19 chapters written by international experts.
Author: Karol Sikora
Publisher: Wiley
ISBN: 9780471925835
Category : Medical
Languages : en
Pages : 364
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Book Description
This work serves as an introduction to the applications of molecular biology in the field of oncology. It provides a basic understanding of the genetic events involved in fully developed human cancer, including research into inherited and acquired gene defects initiating new neoplasms and the subsequent genetic alterations involved in tumor progression. Some of the specific topics explored include gene control, molecular therapy and antibodies, drug resistance, growth factors and receptors, and tumor biology. While intended primarily as an advanced text for oncologists, postgraduate molecular geneticists and molecular biologists, the book will certainly be of interest to other researchers who frequently encounter cancer in their practice.
