Download or read book Regulation of Alternative Splicing and Its Connections to Cancer written by Mo Chen and published by . This book was released on 2011 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: I examined the mechanism of spliceosomal A complex formation and found that SRp38 promotes the recruitment of U1 and U2 snRNPs to splicing substrates that contain high-affinity SRp38 binding sites.
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 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.
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 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 Deciphering the Molecular Mechanism of Alternative Splicing Changes in Cancer written by Taegyun Yang and published by . This book was released on 2023 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Alternative splicing (AS) is an elaborately regulated molecular process incorporating different exons, expanding the proteome diversity from a single gene. AS is involved in virtually all biological processes and diseases, in which the AS process is often dysregulated. Dysregulated AS in cancer is so prevalent that it is now considered a hallmark of cancer. This dysregulation introduces a novel modality to target cancer through splicing modulation. Recent developments in RNA-Sequencing technologies have enabled transcriptome-wide quantification of AS changes in biological processes and diseases, requiring the development of computational methods for deciphering the molecular regulatory mechanisms for the observed AS changes in biological processes, diseases, and treatments.AS process is regulated by multitudes of RNA binding proteins (RBPs), each playing unique roles in the splicing processes, where molecular changes in RBPs causes AS changes in biological processes. Thus, the mechanism of AS changes can be attributed to molecular changes in RBPs, but determining the causal RBPs, based on the observed AS changes, has been challenging due to the complexity of AS regulation. We present Splicing Profile Analysis using RBP KD/KO Signatures (SPARKS), a computational framework to infer causal RBPs by quantifying the similarity in AS between the study of interest and the perturbation of RBPs from a large-scale RBP perturbation database. We verified that splicing factor perturbation leads to unique AS changes, which SPARKS leverages to identify causal RBPs. We demonstrated the efficacy of SPARKS in identifying the causal RBPs in RBP perturbation experiments and biological processes with known regulatory mechanisms in AS. We applied SPARKS to the AS changes in AML patients with the recurrent somatic mutation in U2AF1 and uncovered that the mutant U2AF1 and PTBP1 are involved in the AS changes. We also discovered the candidate RBPs responsible for pan-cancer AS changes upon PRMT5 inhibition therapy, EFTUD2, PCBP2, and PRPF8. Integrating the molecular changes on the candidate RBPs, we generated a potential model for the mechanism of action for PRMT5 inhibition in splicing. In summary, this work illustrates a computational analysis framework to decipher the molecular mechanisms of alternative splicing regulation in biology, disease, and therapy.
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 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 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 Regulation Through Splice Modulation written by Kelsey Trieger and published by . This book was released on 2021 with total page 179 pages. Available in PDF, EPUB and Kindle. Book excerpt: RNA splicing plays a central role in cell regulation, development, and disease progression, but the complexity of this macromolecular assembly process has left RNA splicing underexplored in cancer. In recent years, it has become clear that alternative RNA splicing becomes mis-regulated in and plays a role in the progression of a wide range of cancers. Therefore, drugs that regulate RNA splicing could serve as powerful therapeutics for cancer. Splice modulators (SPLMs) are a class of chemotherapeutics that regulate aberrant splicing profiles in tumors, thereby inducing tumor cell apoptosis. SPLMs interfere with the overused splicing machinery that cancer cells become dependent upon for expansion, thereby limiting the tumor's ability to produce proteins necessary for growth and survival. Understanding the relationship between splicing and cancer progression will allow for expansion of our therapeutic arsenal in tackling cancer. In my graduate studies, I evaluated splice modulator regulation of the cell cycle genes Aurora kinase (AURK) and Polo-like kinase 1 (PLK-1). Next, I leveraged the SPLM FD-895's regulation of the cell cycle to develop a splicing-based combination therapy capable of targeting a wide range of tumor types. This co-dosing approach relied on use of the splice modulator FD-895 to reduce cell cycle RNA, followed by treatment with a cell cycle protein inhibitor to further reduce cell cycle protein expression. This combination therapy was found to be effective against a range of tumor types, including cervical, ovarian, and colorectal tumor cell lines, indicating that this approach has wide therapeutic applications. These studies suggest the potential to engage small molecule SPLM pretreatment as a therapeutic tool to edit the levels of therapeutically targeted proteins by mis-splicing their RNAs. SPLM combination therapy may be particularly useful for enhancing clinical agents that suffer from off-target effects or dose-limiting toxicity and could therefore allow for previously abandoned lead molecules (therapeutics) to re-enter the clinic. Next, I synthesized analogs of the splice modulator FD-895 to investigate structure-activity relationships (SARs) for this class of compound. Structural differences from one SPLM to another lead to significant changes in splicing activity based on SPLM orientation within the spliceosome binding pocket. Therefore, although most SPLMs affect the splicing of the same category of genes, each SPLM affects the splicing of individual genes to a different extent. Through these efforts, we have been able to synthesize splice modulators like 17S-FD-895 with enhanced stability compared to their parent natural products.
Download or read book RNA Splicing and Backsplicing Disease and Therapy written by Rosanna Asselta and published by Frontiers Media SA. This book was released on 2020-12-24 with total page 197 pages. Available in PDF, EPUB and Kindle. Book excerpt: This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact.
Download or read book Nuclear pre mRNA Processing in Plants written by A. S. N. Reddy and published by Springer Science & Business Media. This book was released on 2008-04-16 with total page 323 pages. Available in PDF, EPUB and Kindle. Book excerpt: During the last few years, tremendous progress has been made in understanding various aspects of pre-mRNA processing. This book, with contributions from leading scientists in this area, summarizes recent advances in nuclear pre-mRNA processing in plants. It provides researchers in the field, as well as those in related areas, with an up-to-date and comprehensive, yet concise, overview of the current status and future potential of this research in understanding plant biology.
Download or read book Eukaryotic MRNA Processing written by Adrian Krainer and published by IRL Press. This book was released on 1997 with total page 408 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume focuses on the major aspects of post-transcriptional mRNA processing in the nucleus of eukaryotic cells. Each of the described mRNA reactions is required for proper gene expression and can also serve as a control point for regulating the expression of many genes, for example duringembryonic development or in different cell types. The different chapters review the assembly of newly synthesized nuclear mRNA transcripts into hnRNP particles and catalytically active spliceosomes; the structure and mechanism of action of small nuclear ribonucleoprotein particles and proteinfactors that catalyse pre-mRNA splicing in mammalian cells and in yeast; the regulation of gene expression and generation of protein isoform diversity by alternative splicing; the mechanisms of 3' end cleavage and polyadenylation; the architecture of the cell nucleus in relation to these processesand to the localization of the relevant substrates and factors; the diverse mechanisms of RNA processing by ribozymes and their potential relevance for nuclear mRNA processing; the mechanism of spliced-leader addition by trans-splicing in nematodes and trypanosomes; and the process ofinsertion/deletion mRNA editing in kinetoplasmid protozoa. In each chapter, leading researchers have provided detailed, critical reviews of the history, experimental approaches, major advances, current ideas and models, as well as future directions, for each of these active areas of research.
Download or read book Regulation of Tumorigenic Spliced Isoforms in Cancer written by Aixa Sirenia Tapia-Santos and published by . This book was released on 2011 with total page 104 pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: MDM2 negatively regulates the tumor suppressor protein p53 by blocking its transcriptional activation domain and targeting p53 for proteosomal degradation. Upon induction of specific DNA damage and in cancer the MDM2 transcript undergoes drastic exclusion of its internal exons through the process of alternative splicing. This damage induced alternative splicing results in the generation of the most common alternative spliced form identified in human cancers, MDM2-ALT1. As opposed to full length MDM2, MDM2-ALT1 lacks the p53 binding domain which renders this protein isoform incapable of an interaction with the tumor suppressor. However, our lab and others have shown that MDM2-ALT1 is capable of binding full length MDM2 and to sequester it to the cytoplasm. This MDM2-MDM2-ALT1 interaction inhibits the negative regulation exerted by MDM2 over p53. Therefore, MDM2-ALT1 through its interaction with MDM2, mediates a protective program in which p53 is stabilized and cell cycle arrest, DNA repair and/or apoptosis is induced as a consequence. Because the observed role of MDM2-ALT1 in promoting cell proliferation inhibition is inconsistent to its extensive detection in human cancers, we decided to investigate the regulation behind the alternative splicing of MDM2 and also to determine its role in tumorigenesis. We have identified positive and negative exonic splicing regulators of MDM2 using a system of MDM2 minigenes that upon induction of DNA damage parallel the alternative splicing events that take place in a cancer cellular context in which the generation of MDM2-ALT1 is characteristic. To identify the role of MDM2-ALT1 in tumorigenesis we have generated an in vivo mouse model in which the expression of MDM2-ALT1 is restricted to B cells. We report that mice expressing the MDM2-ALT1 transgene show a significant prevalence in the emergence of degenerative joint disease, an inflammatory disorder associated to the clonal expansion of B cells. Further characterization of the expression of MDM2-ALT1 in B cells using our mouse model is still to prove its usefulness in elucidating the role of MDM2-ALT1 in tumorigenesis.
Download or read book Transcription and Splicing written by B. D. Hames and published by Oxford University Press, USA. This book was released on 1988 with total page 238 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book gives a co-ordinated review of our present knowledge of eukaryotic RNA synthesis.
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:
