Download or read book Alternative Splicing and Cancer written by Muzafar A. Macha and published by CRC Press. This book was released on 2024-05-03 with total page 264 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book Alternative Splicing and Cancer explores the crucial role alternative splicing, a post-transcriptional process, plays in human health and diseases, particularly cancer. Diving deep into the complexities of gene expression and protein diversity, the book illuminates how abnormal splicing contributes to aggressive tumor formation, affecting cellular functions such as proliferation, survival, and immune evasion. With a focus on understanding molecular mechanisms, this book unravels potential diagnostic and prognostic targets, opening doors for enhanced anti-cancer treatment efficacy. An indispensable resource for anyone intrigued by the interplay between gene splicing and cancer biology, it paves the way towards innovative therapeutic strategies.
Download or read book Exploring Alternative Splicing in Cancer written by and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Genomic characterization of cancer subtypes became a major research goal worldwide after the release of the complete human genome sequence in 2001. International consortia (e.g. The Cancer Genome Atlas - TCGA) have profiled and analyzed large numbers of human tumors matched to non-malignant tissues and created databases of molecular aberrations at the DNA, RNA, protein and epigenetic level. Research efforts aimed at understanding the molecular determinants of cancer prompted the rapid development of molecularly targeted chemotherapeutics which significantly improved clinical outcomes. Unfortunately, most cancer patients experience disease relapse manifested as recurrence of residual malignant cells which apparently did not respond to treatment regimes. Such cells either already carried or acquired genetic alterations (e.g. mutation, gene amplification, gene deletion or chromosomal translocation) that provide a clonal advantage to survive under selective therapeutic pressure. DNA aberrations have largely been documented to activate and drive oncogenic transformation as well as modulate response to therapy. Recent evidence highlighted the connection between alternative pre-mRNA splicing, cancer development and response to therapy. Alternative splicing is the essential process in eukaryotic gene expression by which non-coding intron sequences are removed from the pre-mRNA transcripts and specific exons are included or excluded from mature mRNAs. The aim of this thesis is to unravel the role of altered splicing in drug-resistant pediatric leukemia and evaluate the efficacy of small molecule splicing modulators in rare and aggressive tumors which pose major therapeutic challenges in the adult population. Chapter 2 is an extensive overview of the latest findings in the field of alternative splicing regulation in cancer.
Download or read book Alternative Splicing in Cancer written by and published by . This book was released on 2006 with total page 309 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Exploring Alternative Splicing in Prostate Cancer written by Prabhakar Rajan and published by . This book was released on 2008 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Exploring the Pathogenic and Therapeutic Implications of Aberrant Splicing in Breast Cancer written by and published by . This book was released on 2009 with total page 47 pages. Available in PDF, EPUB and Kindle. Book excerpt: In this proposal, we set out to a) systematically monitor splicing variant profiles in breast cancer susceptibility genes and b) explore the role of alternative splicing in breast chemotherapy using a global strategy. In doing so, we hope to identify and validate candidate splicing variants involved in tumorigenesis using polony digital exon-profiling and functional assays. We are moving forward on four fronts - 1) the barcode methodology is in development; 2) we are working with state-of-the art capture arrays; 3) we are using the very latest RNA sequencing technology and 4) we are conducting comprehensive analyses of existing splice site variants in known breast cancer susceptibility genes. In part 3, we have generated over 5 million reads that have been aligned to the splice junction libraries, and we are using these reads to quantify and characterize alternative splicing events. Moreover, we will add value to this project by attempting to identify fusion proteins. In part 4, we have determined that the BRCA2 isoform known as BRCA2deltaex12 is not associated with a recognizable phenotype. This work is now in press in Human Mutation.
Download or read book Elucidating Mechanisms of Alternative Splicing in Cancer and Cellular Stress written by Matias Ignacio Montes Serey and published by . This book was released on 2021 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Alternative splicing of the pre-mRNA is an essential post-transcriptional process in eukaryotes that generates multiple protein isoforms from a single gene. However, this process can be disrupted by mutations leading to several diseases including cancer. One such example is the oncogene and negative regulator of p53 Mouse Double Minute 2 homolog (MDM2), which undergoes alternative splicing to produce a splice isoform that has novel implications in cancer development. MDM2-Alt1 comprised of coding exons 3 and 12, is highly expressed in several cancers including those of the breast, liposarcomas, high-grade gliomas and rhabdomyosarcomas (RMS), and can be induced by genotoxic stress. Another good example of cancer-related aberrant alternative splicing, is the insulin receptor gene (INSR), comprised of 22 exons, and that skipping of the exon 11 allows the production of the IR-A splice isoform. Overexpression of the IR-A isoform compared to the full-length IR-B isoform, has been reported in several cancers including RMS, osteosarcoma, breast cancer, prostate cancer and hepatocellular carcinoma. Understanding of the splicing mechanisms of these two genes is crucial to improve current cancer therapies. In this work we report that SRSF2 positively regulates the alternative splicing of MDM2 and that its binding to the exon 11 can be modulated to generate novel mouse model for cancer studies. Furthermore, we show a novel and unique regulatory mechanism of splicing wherein a nuclear microRNA, miR-29b, influences the alternative splicing of MDM2 by directly binding to the MDM2 pre-mRNA. We show that miR-29b is downregulated by genotoxic stress, a similar characteristic of cancer cells. Finally, we study the usage of antisense oligonucleotides (ASOs) as cancer therapies, by blocking the binding of the CUG-BP1 (CUG Binding Protein 1) splicing factor with an ASO, we promote the alternative splicing of the IR-B isoform which decreases cell proliferation and angiogenesis. Moreover, modulation of the MBNL1 (Muscleblind Like 1) intronic splicing enhancer in the intron 11 of the INSR, set the foundation for a novel mouse model to study this aberrant alternative splicing. Overall, our study underscores the importance of understanding alternative splicing in cancer research, moreover, it expands the knowledge regarding the complex splicing mechanisms involved in disease and finally set the foundations for the design of novel and effective splice-switching cancer therapies.
Download or read book Cancer Stem Cells written by Federica Papaccio and published by Springer Nature. This book was released on with total page 263 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book The Splice is Not Right written by Reyka Glencora Jayasinghe and published by . This book was released on 2018 with total page 240 pages. Available in PDF, EPUB and Kindle. Book excerpt: Accurate interpretation of cancer mutations in individual tumors is a prerequisite for precision medicine. Large-scale sequencing studies, such as The Cancer Genome Atlas (TCGA) project, have worked to address the functional consequences of genomic mutations, with the larger goal of determining the underlying mechanisms of cancer initiation and progression. Many studies have focused on characterizing non-synonymous somatic mutations that alter amino acid sequence, as well as splice disrupting mutations at splice donors and acceptors. Current annotation methods typically classify mutations as disruptors of splicing if they fall on the consensus intronic dinucleotide splice donor, GT, the splice acceptor, AG. Splice site mutations as a group have been presumed to be invariably deleterious because of their disruption of the conserved sequences that are used to identify exon-intron boundaries. While this classification method has been useful, increasing evidence suggests that splice site mutations can lead to transcriptional changes beyond disruption and that many exonic mutations that act primarily through alternative splicing are still being overlooked in cancer genomics. My thesis work focuses on developing tools to systematically classify and functionally validate splice site and splice creating mutations using RNA-Seq data, to more accurately understand the functional consequences of mutations on alternative splicing by integrating DNA and RNA-Sequencing data.First we developed SpliceInator, a semi-automated tool to systematically detect splicing phenotypes using mutation and gene expression data. We interrogated 1,146 conserved splice site mutations across 19 cancer types revealing a wide range of complex splicing phenotypes and emphasize the importance of analyzing patient specific RNA-Sequencing. We further explored beyond the splice site by interogating all mutations in a splicing context using MiSplice for the first large-scale discovery of splice-creating mutations (SCMs) across 8,656 TCGA tumors. We reported 1,964 originally mis-annotated mutations having clear evidence of creating novel splice junctions. Mutations in a subset of genes including PARP1, BRCA1, and BAP1, were experimentally validated for splice-creating function using a mini-gene splicing assay. Notably, we found neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Our work highlights importance of integrating DNA and RNA data for understanding functional and clinical implications of mutations in human diseases. Finally, to further capture the full landscape of SCMs, we explored both somatic and germline mutations for splice-site-creating function using MiSplice. Altogether, we have gathered a set of 2,888 SCMs enabling us to effectively compare the landscape of rare and germline SCMs. This compendium of SCMs has also started to elucidate novel genomic properties of mutations located at the donor and acceptor splice site and SCM containing exons including an overall decrease in the size of the novel exon post mutation, mimicking a natural evolutionary selective pressure but exploited in the cancer genome to maintain proper alternative splicing. To date, this is the first analysis comparing rare germline SCMs and somatic SCMs revealing their comparable dysregulation to the splicing code in cancer. Together my thesis work revealed that splice-site-creating mutants play a much larger role than previously appreciated in contributing to cancer and further expands our understanding of the genetic basis by which mutations can alter the mRNA landscape by dysregulating alternative splicing. More broadly, my work calls for a deeper analysis of seemingly "silent" mutations in any disease as such mutations may alter gene function via alternative splicing and integrating RNA and DNA-Seq can allow for accurate evaluation of mutations in a splicing context.
Download or read book RNA Worlds New Tools for Deep Exploration written by Thomas R. Cech and published by . This book was released on 2018-12-31 with total page 580 pages. Available in PDF, EPUB and Kindle. Book excerpt: "A Subject Collection from Cold Spring Harbor Perspectives in Biology."
Download or read book Alternative Splicing and Disease written by Philippe Jeanteur and published by Springer Science & Business Media. This book was released on 2006-10-04 with total page 265 pages. Available in PDF, EPUB and Kindle. Book excerpt: Splicing of primary RNA transcript is a quasi-systematic step of gene expression in higher organisms. This is the first book to highlight the medical implications, i.e. diseases, caused by alternative splicing. Alternative splicing not only vastly increases protein diversity but also offers numerous opportunities for aberrant splicing events with pathological consequences. The book also outlines possible targets for therapy.
Download or read book Human Cell Transformation written by Johng S. Rhim and published by Springer Nature. This book was released on 2019-10-01 with total page 246 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book, part contributed volume, part proceedings, discusses state-of-the-art advances on human cell transformation in cell models for the study of cancer and aging. Several of the chapters are from the Human Cell Transformation: Advances in Cell Models for the Study of Cancer and Aging conference that was held in June 2018 at McGill University. The authors represent international expertise on a wide variety of topics ranging from different types of cancer (prostate, bone, breast, etc.) to tumor microenvironment, tumor progression, homogeneity, and possible therapies and treatments.
Download or read book Brain Transcriptome written by and published by Academic Press. This book was released on 2014-08-26 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Published since 1959, International Review of Neurobiology is a well-known series appealing to neuroscientists, clinicians, psychologists, physiologists, and pharmacologists. Led by an internationally renowned editorial board, this important serial publishes both eclectic volumes made up of timely reviews and thematic volumes that focus on recent progress in a specific area of neurobiology research. This volume, concentrates on the brain transcriptome.
Download or read book Visualizing RNA Dynamics in the Cell written by and published by Academic Press. This book was released on 2016-05-27 with total page 412 pages. Available in PDF, EPUB and Kindle. Book excerpt: Methods in Enzymology: Visualizing RNA Dynamics in the Cell continues the legacy of this premier serial with quality chapters authored by leaders in the field. This volume covers research methods visualizing RNA dynamics in the cell, and includes sections on such topics as identification of RNA cis-regulatory sequences, IRAS, IMAGEtags, MERFISH, plant RNA labeling using MS2, and visualization of 5S dynamics in live cells using photostable corn probe. Continues the legacy of this premier serial with quality chapters authored by leaders in the field Covers research methods in visualizing RNA dynamics in the cell Contains sections on such topics as identification of RNA cis-regulatory sequences, IRAS, IMAGEtags, MERFISH, plant RNA labeling using MS2 and visualization of 5S dynamics in live cells using photostable corn probe
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.
Download or read book Tumor Microenvironment written by Jacinta Serpa and published by Springer Nature. This book was released on 2020-03-04 with total page 430 pages. Available in PDF, EPUB and Kindle. Book excerpt: The way a cell undergoes malignant transformation should meet their capacity of surviving in the microenvironment of the organ where the cancer will develop. Metabolic adaptation is for sure one of the criteria that must be accomplished, driven by metabolic plasticity that allows the adaptation of cancer cells to the availability of energy and biomass sources that will sustain cell survival and proliferation. Each human organ has a particular microenvironment which depends on several cell types and in some cases also on symbiotic microorganisms. These biological partners are constantly sharing organic compounds and signaling molecules that will control mitogenesis, cell death and differentiation, accounting for the organ's function. Nevertheless, cancer cells are capable of taking advantage of this metabolic and signaling microenvironmental dynamics. In this book, we intend to present the different components of the microenvironment driving the metabolic fitness of cancer cells. The metabolic changes required for establishing a tumor in a given microenvironment and how these metabolic changes limit the response to drugs will generally be the major items addressed. It is important to mention not only aspects of the microenvironment that stimulate metabolic changes and that select better adapted tumor cells, but also how this regulation of cell plasticity is made. Thus, the signaling pathways that orchestrate and are orchestrated throughout this panoply of metabolic rearrangements will also be addressed in this book. The subjects will be presented from the conceptual point of view of the cross-cancer mechanisms and also particularizing some models that can be examples and enlightening within the different areas.
Download or read book Molecular Biology of RNA written by David Elliott and published by Oxford University Press. This book was released on 2017-01-31 with total page 445 pages. Available in PDF, EPUB and Kindle. Book excerpt: RNA plays a central, and until recently, somewhat underestimated role in the genetics underlying all forms of life on earth. This versatile molecule not only plays a crucial part in the synthesis of proteins from a DNA template, but is also intrinsically involved in the regulation of gene expression, and can even act as a catalyst in the form of a ribozyme. This latter property has led to the hypothesis that RNA - rather than DNA - could have played an essential part in the origin of life itself. This landmark text provides a systematic overview of the exciting and rapidly moving field of RNA biology. Key pioneering experiments, which provided the underlying evidence for what we now know, are described throughout, while the relevance of the subject to human disease is highlighted via frequent boxes. For the second edition of Molecular Biology of RNA, more introductory material has been incorporated at the beginning of the text, to aid students studying the subject for the first time. Throughout the text, new material has been included - particularly in relation to RNA binding domains, non-coding RNAs, and the connection between RNA biology and epigenetics. Finally, a new closing chapter discusses how exciting new technologies are being used to explore current topical areas of research.
Download or read book Regulation of Alternative Splicing written by Philippe Jeanteur and published by Springer Science & Business Media. This book was released on 2002-10-21 with total page 272 pages. Available in PDF, EPUB and Kindle. Book excerpt: The discovery in 1977 that genes are split into exons and introns has done away with the one gene - one protein dogma. Indeed, the removal of introns from the primary RNA transcript is not necessarily straightforward since there may be optional pathways leading to different messenger RNAs and consequently to different proteins. Examples of such an alternative splicing mechanism cover all fields of biology. Moreover, there are plenty of occurrences where deviant splicing can have pathological effects. Despite the high number of specific cases of alternative splicing, it was not until recently that the generality and extent of this phenomenon was fully appreciated. A superficial reading of the preliminary sequence of the human genome published in 2001 led to the surprising, and even deceiving to many scientists, low number of genes (around 32,000) which contrasted with the much higher figure around 150,000 which was previously envisioned. Attempts to make a global assessment of the use of alternative splicing are recent and rely essentially on the comparison of genomic mRNA and EST sequences as reviewed by Thanaraj and Stamm in the first chapter of this volume. Most recent estimates suggest that 40-60% of human genes might be alternatively spliced, as opposed to about 22% for C. elegans.
