A Novel Knock-Out Animal Model to Analyze Transcriptional Signaling by P53 Tumor Suppressor Protein in Breast Cancer PDF Download
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Author: Gokul M. Das
Publisher:
ISBN:
Category :
Languages : en
Pages : 16
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Book Description
Two important transcriptional targets of p53 tumor suppressor protein are genes encoding the Proliferating Cell Nuclear Antigen (PCNA) and p21/WAF1/Cip1. PCNA is a necessary component of DNA replication and DNA repair machinery. p21/WAF1/Cip1 is a cyclin-dependent kinase (cdk) inhibitor which can interact with PCNA to modulate the balance of DNA repair versus replication. We hypothesize that correct ratio of PCNA and p21 proteins is crucial for normal regulation of DNA repair and cell cycle control, and hence, disregulation of PCNA and p21 transcription in response to genomic damage is an important aspect of breast cancer formation. To test this hypothesis in vivo, we are developing a mouse model where p53 signaling specifically to the PCNA and p21 gene transcription is disrupted. Toward this goal, we are characterizing p53 interaction sites on mouse p21 and PCNA gene promoters (from a series of BAC clones isolated with the help of Poswell Park Cancer Institute Microarray and Genomics Facility). This mouse model will enable testing the relevance of specific transcriptional signaling by p53 to mammary oncogenesis, identification of new therapeutic targets, and analyzing the role of specific p53 transcriptional targets in modulating responses to chemotherapeutic drugs and radiation therapy.
Author: Gokul M. Das
Publisher:
ISBN:
Category :
Languages : en
Pages : 16
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Book Description
Two important transcriptional targets of p53 tumor suppressor protein are genes encoding the Proliferating Cell Nuclear Antigen (PCNA) and p21/WAF1/Cip1. PCNA is a necessary component of DNA replication and DNA repair machinery. p21/WAF1/Cip1 is a cyclin-dependent kinase (cdk) inhibitor which can interact with PCNA to modulate the balance of DNA repair versus replication. We hypothesize that correct ratio of PCNA and p21 proteins is crucial for normal regulation of DNA repair and cell cycle control, and hence, disregulation of PCNA and p21 transcription in response to genomic damage is an important aspect of breast cancer formation. To test this hypothesis in vivo, we are developing a mouse model where p53 signaling specifically to the PCNA and p21 gene transcription is disrupted. Toward this goal, we are characterizing p53 interaction sites on mouse p21 and PCNA gene promoters (from a series of BAC clones isolated with the help of Poswell Park Cancer Institute Microarray and Genomics Facility). This mouse model will enable testing the relevance of specific transcriptional signaling by p53 to mammary oncogenesis, identification of new therapeutic targets, and analyzing the role of specific p53 transcriptional targets in modulating responses to chemotherapeutic drugs and radiation therapy.
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 16
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Book Description
The p53 and pRb tumor suppressor pathways are frequently altered in human breast cancer. Although animal models have begun to explore mechanisms for these proteins, the roles can be different depending on the cancer type. Our previous studies in a mouse brain epithelial tumor model have demonstrated the importance of pRb in tumor initiation and of p53 in tumor progression, and have established p53-dependent apoptosis as a means of tumor suppression. In this model, brain cells are induced to proliferate aberrantly by tissue-specific expression of T121, a small T antigen oncoprotein that inactivates pRb. This causes slow growing, but highly apoptotic tumors. Further inactivation of p53 causes a dramatic decline in cell death and rapid acceleration of tumor growth. We propose similar studies to examine the pRb and p53 roles in breast cancer. The full T antigen oncoprotein (inactivates both pRb and p53) has been shown to induce mammary tumors in transgenic mice. Here, the T - oncoprotein will be tissue-specifically expressed in mammary epithelium by mammary-specific promoters to test the role of pRb.
Author: Jeffrey E. Green
Publisher: Springer Science & Business Media
ISBN: 0387698051
Category : Medical
Languages : en
Pages : 639
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Book Description
Genetically-engineered mouse models for cancer research have become invaluable tools for studying cancer biology and evaluating novel therapeutic approaches. This volume focuses on state-of-the-art methods for generating, analyzing and validating such models for studying aspects of human cancer biology. Additionally, these models are emerging as important pre-clinical systems in which to test cancer prevention and therapeutic strategies in order to select compounds for testing in clinical trials.
Author: Guillermina Lozano
Publisher:
ISBN: 9781621821335
Category : Medical
Languages : en
Pages : 0
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Book Description
Decades of research on the tumor suppressor p53 have revealed that it plays a significant role as a "guardian of the genome," protecting cells against genotoxic stress. In recent years, p53 research has begun to move into the clinic in attempts to understand how p53 is frequently inactivated in-and sometimes even promotes-human cancer. Written and edited by experts in the field, this collection from Cold Spring Harbor Perspectives in Medicine covers the rapid progress that has recently been made in basic and clinical research on p53. The contributors review new observations about its basic biology, providing updates on the functions of its isoforms and domains, the myriad stresses and signals that trigger its activation or repression, and its downstream effects on genome stability and the cell cycle that enforce tumor suppression in different cell and tissue types. They also discuss how p53 dysfunction contributes to cancer, exploring the various inherited and somatic mutations in the human TP53 gene, the impact of mutant p53 proteins on tumorigenesis, and the prognostic value and clinical outcomes of these mutations. Drugs that are being developed to respond to tumors harboring aberrant p53 are also described. This book is therefore essential reading for all cancer biologists, cell and molecular biologists, and pharmacologists concerned with the treatment of this disease.
Author: Hiroshi Hiai
Publisher: Karger Medical and Scientific Publishers
ISBN: 3805567197
Category : Medical
Languages : en
Pages : 184
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Book Description
This book brings together some of the most recent advances made in the genetic analysis of cancer susceptibility using animal models. Leading investigators in the field present model systems for studying cancers including liver and stomach cancer, breast cancer, myeloid leukemia, retrovirus-induced lymphoma, pulmonary adenoma and familial adenomatous polyposis. An overview of transgenic and gene knockout mice is given, and in several chapters the implications of these findings for human cancers are discussed. The book is recommended reading for all scientists and graduate students in experimental cancer research and cancer genomics.
Author: Kristen Lynn Murphy
Publisher:
ISBN:
Category :
Languages : en
Pages : 446
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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: Lawrence Donehower
Publisher:
ISBN:
Category :
Languages : en
Pages : 69
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Book Description
The p53 tumor suppressor gene is mutated in about half of all human cancers and in roughly 30-40% of breast cancers. In order to better understand the role of p53 mutation and loss in breast cancer progression, we have developed a mouse model which is genetically programmed to develop mammary cancer in the presence and absence of p53. By comparison of the mammary tumorigenesis process between the p53 positive and p53 negative animals we hope to obtain further insights into the mechanisms by which loss of p53 accelerates tumor progression. In the first three years of this grant we have shown that in the absence of p53 mammary tumors arise sooner and grow faster than mammary tumors with intact p53. We have also shown that tumors without p53 have higher levels of chromosomal instability and higher rates of cell proliferation than tumors with p53. Rates of apoptosis (programmed cell death) and angiogenesis (tumor vascularization) were not significantly different between p53 positive and negative tumors. We have examined the role of the p53-inducible cyclin-dependent kinase inhibitor p21 in mammary tumor progression and have shown that reduction of p21 accelerates tumor cell proliferation rates. Thus, the model is useful in elucidating the role of p53 loss in tumorigenesis and indicates that p53 has multiple roles in prevention of tumor formation and progression.
Author: Keiko Hiyama
Publisher: Springer Science & Business Media
ISBN: 1603278796
Category : Medical
Languages : en
Pages : 375
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Book Description
Telomerase, an enzyme that maintains telomeres and endows eukaryotic cells with immortality, was first discovered in tetrahymena in 1985. In 1990s, it was proven that this enzyme also plays a key role in the infinite proliferation of human cancer cells. Now telomere and telomerase are widely accepted as important factors involved in cancer biology, and as promising diagnostic tools and therapeutic targets. Recently, role of telomerase in “cancer stem cells” has become another attractive story. Until now, there are several good books on telomere and telomerase focusing on biology in ciliates, yeasts, and mouse or basic sciences in human, providing basic scientists or students with updated knowledge.
Author:
Publisher:
ISBN: 9780815332183
Category : Cells
Languages : en
Pages : 0
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Book Description
Author: Igor Kovalchuk
Publisher: Academic Press
ISBN: 0323856802
Category : Science
Languages : en
Pages : 762
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Book Description
Genome Stability: From Virus to Human Application, Second Edition, a volume in the Translational Epigenetics series, explores how various species maintain genome stability and genome diversification in response to environmental factors. Here, across thirty-eight chapters, leading researchers provide a deep analysis of genome stability in DNA/RNA viruses, prokaryotes, single cell eukaryotes, lower multicellular eukaryotes, and mammals, examining how epigenetic factors contribute to genome stability and how these species pass memories of encounters to progeny. Topics also include major DNA repair mechanisms, the role of chromatin in genome stability, human diseases associated with genome instability, and genome stability in response to aging. This second edition has been fully revised to address evolving research trends, including CRISPRs/Cas9 genome editing; conventional versus transgenic genome instability; breeding and genetic diseases associated with abnormal DNA repair; RNA and extrachromosomal DNA; cloning, stem cells, and embryo development; programmed genome instability; and conserved and divergent features of repair. This volume is an essential resource for geneticists, epigeneticists, and molecular biologists who are looking to gain a deeper understanding of this rapidly expanding field, and can also be of great use to advanced students who are looking to gain additional expertise in genome stability. A deep analysis of genome stability research from various kingdoms, including epigenetics and transgenerational effects Provides comprehensive coverage of mechanisms utilized by different organisms to maintain genomic stability Contains applications of genome instability research and outcomes for human disease Features all-new chapters on evolving areas of genome stability research, including CRISPRs/Cas9 genome editing, RNA and extrachromosomal DNA, programmed genome instability, and conserved and divergent features of repair
