International Journal of Molecular Sciences

16 pages, 862 KiB

Open AccessReview

The Potential Contribution of Dysfunctional RNA-Binding Proteins to the Pathogenesis of Neurodegeneration in Multiple Sclerosis and Relevant Models

by Cole D. Libner, Hannah E. Salapa and Michael C. Levin

Int. J. Mol. Sci. 2020, 21(13), 4571; https://doi.org/10.3390/ijms21134571 - 27 Jun 2020

Cited by 16 | Viewed by 4768

Abstract

Neurodegeneration in multiple sclerosis (MS) is believed to underlie disease progression and permanent disability. Many mechanisms of neurodegeneration in MS have been proposed, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, and RNA-binding protein dysfunction. The purpose of this review is to highlight mechanisms [...] Read more.

Neurodegeneration in multiple sclerosis (MS) is believed to underlie disease progression and permanent disability. Many mechanisms of neurodegeneration in MS have been proposed, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, and RNA-binding protein dysfunction. The purpose of this review is to highlight mechanisms of neurodegeneration in MS and its models, with a focus on RNA-binding protein dysfunction. Studying RNA-binding protein dysfunction addresses a gap in our understanding of the pathogenesis of MS, which will allow for novel therapies to be generated to attenuate neurodegeneration before irreversible central nervous system damage occurs. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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25 pages, 1108 KiB

Open AccessReview

Post-Transcriptional Expression Control in Platelet Biogenesis and Function

by Carolin T. Neu, Tony Gutschner and Monika Haemmerle

Int. J. Mol. Sci. 2020, 21(20), 7614; https://doi.org/10.3390/ijms21207614 - 15 Oct 2020

Cited by 18 | Viewed by 4429

Abstract

Platelets are highly abundant cell fragments of the peripheral blood that originate from megakaryocytes. Beside their well-known role in wound healing and hemostasis, they are emerging mediators of the immune response and implicated in a variety of pathophysiological conditions including cancer. Despite their [...] Read more.

Platelets are highly abundant cell fragments of the peripheral blood that originate from megakaryocytes. Beside their well-known role in wound healing and hemostasis, they are emerging mediators of the immune response and implicated in a variety of pathophysiological conditions including cancer. Despite their anucleate nature, they harbor a diverse set of RNAs, which are subject to an active sorting mechanism from megakaryocytes into proplatelets and affect platelet biogenesis and function. However, sorting mechanisms are poorly understood, but RNA-binding proteins (RBPs) have been suggested to play a crucial role. Moreover, RBPs may regulate RNA translation and decay following platelet activation. In concert with other regulators, including microRNAs, long non-coding and circular RNAs, RBPs control multiple steps of the platelet life cycle. In this review, we will highlight the different RNA species within platelets and their impact on megakaryopoiesis, platelet biogenesis and platelet function. Additionally, we will focus on the currently known concepts of post-transcriptional control mechanisms important for RNA fate within platelets with a special emphasis on RBPs. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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24 pages, 4522 KiB

Open AccessReview

Dicing the Disease with Dicer: The Implications of Dicer Ribonuclease in Human Pathologies

by Eleni I. Theotoki, Vasiliki I. Pantazopoulou, Stella Georgiou, Panos Kakoulidis, Vicky Filippa, Dimitrios J. Stravopodis and Ema Anastasiadou

Int. J. Mol. Sci. 2020, 21(19), 7223; https://doi.org/10.3390/ijms21197223 - 30 Sep 2020

Cited by 24 | Viewed by 6504

Abstract

Gene expression dictates fundamental cellular processes and its de-regulation leads to pathological conditions. A key contributor to the fine-tuning of gene expression is Dicer, an RNA-binding protein (RBPs) that forms complexes and affects transcription by acting at the post-transcriptional level via the targeting [...] Read more.

Gene expression dictates fundamental cellular processes and its de-regulation leads to pathological conditions. A key contributor to the fine-tuning of gene expression is Dicer, an RNA-binding protein (RBPs) that forms complexes and affects transcription by acting at the post-transcriptional level via the targeting of mRNAs by Dicer-produced small non-coding RNAs. This review aims to present the contribution of Dicer protein in a wide spectrum of human pathological conditions, including cancer, neurological, autoimmune, reproductive and cardiovascular diseases, as well as viral infections. Germline mutations of Dicer have been linked to Dicer1 syndrome, a rare genetic disorder that predisposes to the development of both benign and malignant tumors, but the exact correlation of Dicer protein expression within the different cancer types is unclear, and there are contradictions in the data. Downregulation of Dicer is related to Geographic atrophy (GA), a severe eye-disease that is a leading cause of blindness in industrialized countries, as well as to psychiatric and neurological diseases such as depression and Parkinson’s disease, respectively. Both loss and upregulation of Dicer protein expression is implicated in severe autoimmune disorders, including psoriasis, ankylosing spondylitis, rheumatoid arthritis, multiple sclerosis and autoimmune thyroid diseases. Loss of Dicer contributes to cardiovascular diseases and causes defective germ cell differentiation and reproductive system abnormalities in both sexes. Dicer can also act as a strong antiviral with a crucial role in RNA-based antiviral immunity. In conclusion, Dicer is an essential enzyme for the maintenance of physiology due to its pivotal role in several cellular processes, and its loss or aberrant expression contributes to the development of severe human diseases. Further exploitation is required for the development of novel, more effective Dicer-based diagnostic and therapeutic strategies, with the goal of new clinical benefits and better quality of life for patients. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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14 pages, 1703 KiB

Open AccessReview

MCPIP1 RNase and Its Multifaceted Role

by Richard Musson, Weronika Szukała and Jolanta Jura

Int. J. Mol. Sci. 2020, 21(19), 7183; https://doi.org/10.3390/ijms21197183 - 29 Sep 2020

Cited by 20 | Viewed by 4180

Abstract

Inflammation is an organism’s physiological response to harmful septic and aseptic stimuli. This process begins locally through the influx of immune system cells to the damaged tissue and the subsequent activation and secretion of inflammatory mediators to restore homeostasis in the organism. Inflammation [...] Read more.

Inflammation is an organism’s physiological response to harmful septic and aseptic stimuli. This process begins locally through the influx of immune system cells to the damaged tissue and the subsequent activation and secretion of inflammatory mediators to restore homeostasis in the organism. Inflammation is regulated at many levels, and one of these levels is post-transcriptional regulation, which controls the half-life of transcripts that encode inflammatory mediators. One of the proteins responsible for controlling the amount of mRNA in a cell is the RNase monocyte chemoattractant protein-induced protein 1 (MCPIP1). The studies conducted so far have shown that MCPIP1 is involved not only in the regulation of inflammation but also in many other physiological and pathological processes. This paper provides a summary of the information on the role of MCPIP1 in adipogenesis, angiogenesis, cell differentiation, cancer, and skin inflammation obtained to date. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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16 pages, 1533 KiB

Open AccessReview

The Emerging Role of the RNA-Binding Protein SFPQ in Neuronal Function and Neurodegeneration

by Yee Wa Lim, Dylan James, Jie Huang and Mihwa Lee

Int. J. Mol. Sci. 2020, 21(19), 7151; https://doi.org/10.3390/ijms21197151 - 28 Sep 2020

Cited by 34 | Viewed by 7375

Abstract

RNA-binding proteins (RBPs) are a class of proteins known for their diverse roles in RNA biogenesis, from regulating transcriptional processes in the nucleus to facilitating translation in the cytoplasm. With higher demand for RNA metabolism in the nervous system, RBP misregulation has been [...] Read more.

RNA-binding proteins (RBPs) are a class of proteins known for their diverse roles in RNA biogenesis, from regulating transcriptional processes in the nucleus to facilitating translation in the cytoplasm. With higher demand for RNA metabolism in the nervous system, RBP misregulation has been linked to a wide range of neurological and neurodegenerative diseases. One of the emerging RBPs implicated in neuronal function and neurodegeneration is splicing factor proline- and glutamine-rich (SFPQ). SFPQ is a ubiquitous and abundant RBP that plays multiple regulatory roles in the nucleus such as paraspeckle formation, DNA damage repair, and various transcriptional regulation processes. An increasing number of studies have demonstrated the nuclear and also cytoplasmic roles of SFPQ in neurons, particularly in post-transcriptional regulation and RNA granule formation. Not surprisingly, the misregulation of SFPQ has been linked to pathological features shown by other neurodegenerative disease-associated RBPs such as aberrant RNA splicing, cytoplasmic mislocalization, and aggregation. In this review, we discuss recent findings on the roles of SFPQ with a particular focus on those in neuronal development and homeostasis as well as its implications in neurodegenerative diseases. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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30 pages, 1750 KiB

Open AccessReview

Expression, Regulation and Function of microRNA as Important Players in the Transition of MDS to Secondary AML and Their Cross Talk to RNA-Binding Proteins

by Marcus Bauer, Christoforos Vaxevanis, Nadine Heimer, Haifa Kathrin Al-Ali, Nadja Jaekel, Michael Bachmann, Claudia Wickenhauser and Barbara Seliger

Int. J. Mol. Sci. 2020, 21(19), 7140; https://doi.org/10.3390/ijms21197140 - 27 Sep 2020

Cited by 19 | Viewed by 4271

Abstract

Myelodysplastic syndromes (MDS), heterogeneous diseases of hematopoietic stem cells, exhibit a significant risk of progression to secondary acute myeloid leukemia (sAML) that are typically accompanied by MDS-related changes and therefore significantly differ to de novo acute myeloid leukemia (AML). Within these disorders, the [...] Read more.

Myelodysplastic syndromes (MDS), heterogeneous diseases of hematopoietic stem cells, exhibit a significant risk of progression to secondary acute myeloid leukemia (sAML) that are typically accompanied by MDS-related changes and therefore significantly differ to de novo acute myeloid leukemia (AML). Within these disorders, the spectrum of cytogenetic alterations and oncogenic mutations, the extent of a predisposing defective osteohematopoietic niche, and the irregularity of the tumor microenvironment is highly diverse. However, the exact underlying pathophysiological mechanisms resulting in hematopoietic failure in patients with MDS and sAML remain elusive. There is recent evidence that the post-transcriptional control of gene expression mediated by microRNAs (miRNAs), long noncoding RNAs, and/or RNA-binding proteins (RBPs) are key components in the pathogenic events of both diseases. In addition, an interplay between RBPs and miRNAs has been postulated in MDS and sAML. Although a plethora of miRNAs is aberrantly expressed in MDS and sAML, their expression pattern significantly depends on the cell type and on the molecular make-up of the sample, including chromosomal alterations and single nucleotide polymorphisms, which also reflects their role in disease progression and prediction. Decreased expression levels of miRNAs or RBPs preventing the maturation or inhibiting translation of genes involved in pathogenesis of both diseases were found. Therefore, this review will summarize the current knowledge regarding the heterogeneity of expression, function, and clinical relevance of miRNAs, its link to molecular abnormalities in MDS and sAML with specific focus on the interplay with RBPs, and the current treatment options. This information might improve the use of miRNAs and/or RBPs as prognostic markers and therapeutic targets for both malignancies. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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28 pages, 1203 KiB

Open AccessReview

RNA-Binding Proteins as Regulators of Migration, Invasion and Metastasis in Oral Squamous Cell Carcinoma

by Jonas Weiße, Julia Rosemann, Vanessa Krauspe, Matthias Kappler, Alexander W. Eckert, Monika Haemmerle and Tony Gutschner

Int. J. Mol. Sci. 2020, 21(18), 6835; https://doi.org/10.3390/ijms21186835 - 17 Sep 2020

Cited by 36 | Viewed by 7949

Abstract

Nearly 7.5% of all human protein-coding genes have been assigned to the class of RNA-binding proteins (RBPs), and over the past decade, RBPs have been increasingly recognized as important regulators of molecular and cellular homeostasis. RBPs regulate the post-transcriptional processing of their target [...] Read more.

Nearly 7.5% of all human protein-coding genes have been assigned to the class of RNA-binding proteins (RBPs), and over the past decade, RBPs have been increasingly recognized as important regulators of molecular and cellular homeostasis. RBPs regulate the post-transcriptional processing of their target RNAs, i.e., alternative splicing, polyadenylation, stability and turnover, localization, or translation as well as editing and chemical modification, thereby tuning gene expression programs of diverse cellular processes such as cell survival and malignant spread. Importantly, metastases are the major cause of cancer-associated deaths in general, and particularly in oral cancers, which account for 2% of the global cancer mortality. However, the roles and architecture of RBPs and RBP-controlled expression networks during the diverse steps of the metastatic cascade are only incompletely understood. In this review, we will offer a brief overview about RBPs and their general contribution to post-transcriptional regulation of gene expression. Subsequently, we will highlight selected examples of RBPs that have been shown to play a role in oral cancer cell migration, invasion, and metastasis. Last but not least, we will present targeting strategies that have been developed to interfere with the function of some of these RBPs. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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14 pages, 1692 KiB

Open AccessReview

The Role of the RNA-Binding Protein Family MEX-3 in Tumorigenesis

by Simon Jasinski-Bergner, André Steven and Barbara Seliger

Int. J. Mol. Sci. 2020, 21(15), 5209; https://doi.org/10.3390/ijms21155209 - 23 Jul 2020

Cited by 15 | Viewed by 3105

Abstract

The muscle excess 3 (MEX-3) protein was first identified in Caenorhabditis elegans (C. elegans), and its respective homologues were also observed in vertebrates, including humans. It is a RNA-binding protein (RBP) with an additional ubiquitin E3 ligase function, which further acts as [...] Read more.

The muscle excess 3 (MEX-3) protein was first identified in Caenorhabditis elegans (C. elegans), and its respective homologues were also observed in vertebrates, including humans. It is a RNA-binding protein (RBP) with an additional ubiquitin E3 ligase function, which further acts as a post-transcriptional repressor through unknown mechanisms. In humans, MEX-3 proteins post-transcriptionally regulate a number of biological processes, including tumor immunological relevant ones. These have been shown to be involved in various diseases, including tumor diseases of distinct origins. This review provides information on the expression and function of the human MEX-3 family in healthy tissues, as well after malignant transformation. Indeed, the MEX-3 expression was shown to be deregulated in several cancers and to affect tumor biological functions, including apoptosis regulation, antigen processing, and presentation, thereby, contributing to the immune evasion of tumor cells. Furthermore, current research suggests MEX-3 proteins as putative markers for prognosis and as novel targets for the anti-cancer treatment. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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27 pages, 2245 KiB

Open AccessArticle

Identification of RNA-Binding Proteins as Targetable Putative Oncogenes in Neuroblastoma

by Jessica L. Bell, Sven Hagemann, Jessica K. Holien, Tao Liu, Zsuzsanna Nagy, Johannes H. Schulte, Danny Misiak and Stefan Hüttelmaier

Int. J. Mol. Sci. 2020, 21(14), 5098; https://doi.org/10.3390/ijms21145098 - 19 Jul 2020

Cited by 15 | Viewed by 4606

Abstract

Neuroblastoma is a common childhood cancer with almost a third of those affected still dying, thus new therapeutic strategies need to be explored. Current experimental therapies focus mostly on inhibiting oncogenic transcription factor signalling. Although LIN28B, DICER and other RNA-binding proteins (RBPs) have [...] Read more.

Neuroblastoma is a common childhood cancer with almost a third of those affected still dying, thus new therapeutic strategies need to be explored. Current experimental therapies focus mostly on inhibiting oncogenic transcription factor signalling. Although LIN28B, DICER and other RNA-binding proteins (RBPs) have reported roles in neuroblastoma development and patient outcome, the role of RBPs in neuroblastoma is relatively unstudied. In order to elucidate novel RBPs involved in MYCN-amplified and other high-risk neuroblastoma subtypes, we performed differential mRNA expression analysis of RBPs in a large primary tumour cohort (n = 498). Additionally, we found via Kaplan–Meier scanning analysis that 685 of the 1483 tested RBPs have prognostic value in neuroblastoma. For the top putative oncogenic candidates, we analysed their expression in neuroblastoma cell lines, as well as summarised their characteristics and existence of chemical inhibitors. Moreover, to help explain their association with neuroblastoma subtypes, we reviewed candidate RBPs’ potential as biomarkers, and their mechanistic roles in neuronal and cancer contexts. We found several highly significant RBPs including RPL22L1, RNASEH2A, PTRH2, MRPL11 and AFF2, which remain uncharacterised in neuroblastoma. Although not all RBPs appear suitable for drug design, or carry prognostic significance, we show that several RBPs have strong rationale for inhibition and mechanistic studies, representing an alternative, but nonetheless promising therapeutic strategy in neuroblastoma treatment. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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12 pages, 2400 KiB

Open AccessArticle

Quantitative Proteomics to Identify Nuclear RNA-Binding Proteins of Malat1

by Marian Scherer, Michal Levin, Falk Butter and Marion Scheibe

Int. J. Mol. Sci. 2020, 21(3), 1166; https://doi.org/10.3390/ijms21031166 - 10 Feb 2020

Cited by 16 | Viewed by 5217

Abstract

The long non-coding RNA Malat1 has been implicated in several human cancers, while the mechanism of action is not completely understood. As RNAs in cells function together with RNA-binding proteins (RBPs), the composition of their RBP complex can shed light on their functionality. [...] Read more.

The long non-coding RNA Malat1 has been implicated in several human cancers, while the mechanism of action is not completely understood. As RNAs in cells function together with RNA-binding proteins (RBPs), the composition of their RBP complex can shed light on their functionality. We here performed quantitative interactomics of 14 non-overlapping fragments covering the full length of Malat1 to identify possible nuclear interacting proteins. Overall, we identified 35 candidates including 14 already known binders, which are able to interact with Malat1 in the nucleus. Furthermore, the use of fragments along the full-length RNA allowed us to reveal two hotspots for protein binding, one in the 5′-region and one in the 3′-region of Malat1. Our results provide confirmation on previous RNA-protein interaction studies and suggest new candidates for functional investigations. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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17 pages, 2783 KiB

Open AccessArticle

YBX1 Indirectly Targets Heterochromatin-Repressed Inflammatory Response-Related Apoptosis Genes through Regulating CBX5 mRNA

by Andreas Kloetgen, Sujitha Duggimpudi, Konstantin Schuschel, Kebria Hezaveh, Daniel Picard, Heiner Schaal, Marc Remke, Jan-Henning Klusmann, Arndt Borkhardt, Alice C. McHardy and Jessica I. Hoell

Int. J. Mol. Sci. 2020, 21(12), 4453; https://doi.org/10.3390/ijms21124453 - 23 Jun 2020

Cited by 14 | Viewed by 3542

Abstract

Medulloblastomas arise from undifferentiated precursor cells in the cerebellum and account for about 20% of all solid brain tumors during childhood; standard therapies include radiation and chemotherapy, which oftentimes come with severe impairment of the cognitive development of the young patients. Here, we [...] Read more.

Medulloblastomas arise from undifferentiated precursor cells in the cerebellum and account for about 20% of all solid brain tumors during childhood; standard therapies include radiation and chemotherapy, which oftentimes come with severe impairment of the cognitive development of the young patients. Here, we show that the posttranscriptional regulator Y-box binding protein 1 (YBX1), a DNA- and RNA-binding protein, acts as an oncogene in medulloblastomas by regulating cellular survival and apoptosis. We observed different cellular responses upon YBX1 knockdown in several medulloblastoma cell lines, with significantly altered transcription and subsequent apoptosis rates. Mechanistically, PAR-CLIP for YBX1 and integration with RNA-Seq data uncovered direct posttranscriptional control of the heterochromatin-associated gene CBX5; upon YBX1 knockdown and subsequent CBX5 mRNA instability, heterochromatin-regulated genes involved in inflammatory response, apoptosis and death receptor signaling were de-repressed. Thus, YBX1 acts as an oncogene in medulloblastoma through indirect transcriptional regulation of inflammatory genes regulating apoptosis and represents a promising novel therapeutic target in this tumor entity. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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17 pages, 2724 KiB

Open AccessArticle

RNA Binding Proteins as Drivers and Therapeutic Target Candidates in Pancreatic Ductal Adenocarcinoma

by Markus Glaß, Patrick Michl and Stefan Hüttelmaier

Int. J. Mol. Sci. 2020, 21(11), 4190; https://doi.org/10.3390/ijms21114190 - 11 Jun 2020

Cited by 18 | Viewed by 3664

Abstract

Pancreatic ductal adenocarcinomas (PDAC) belong to the most frequent and most deadly malignancies in the western world. Mutations in KRAS and TP53 along with some other frequent polymorphisms occur almost universally and are likely to be responsible for tumor initiation. However, these mutations [...] Read more.

Pancreatic ductal adenocarcinomas (PDAC) belong to the most frequent and most deadly malignancies in the western world. Mutations in KRAS and TP53 along with some other frequent polymorphisms occur almost universally and are likely to be responsible for tumor initiation. However, these mutations cannot explain the heterogeneity in therapeutic responses observed in PDAC patients, which limits efficiency of current therapeutic strategies. Instead, recent classifications of PDAC tumor samples are based on transcriptomics data and thus include information about epigenetic, transcriptomic, and post-transcriptomic deregulations. RNA binding proteins (RBPs) are important post-transcriptional regulators involved in every aspect of the RNA life cycle and thus considerably influence the transcriptome. In this study, we systematically investigated deregulated expression, prognostic value, and essentiality reported for RBPs in PDAC or PDAC cancer models using publicly available data. We identified 44 RBPs with suggested oncogenic potential. These include various proteins, e.g., IGF2 mRNA binding proteins (IGF2BPs), with reported tumor-promoting roles. We further characterized these RBPs and found common patterns regarding their expression, interaction, and regulation by microRNAs. These analyses suggest four prime candidate oncogenic RBPs with partially validated target potential: APOBEC1, IGF2BP1 and 3, and OASL. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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30 pages, 3492 KiB

Open AccessReview

From the Argonauts Mythological Sailors to the Argonautes RNA-Silencing Navigators: Their Emerging Roles in Human-Cell Pathologies

by Vasiliki I. Pantazopoulou, Stella Georgiou, Panos Kakoulidis, Stavroula N. Giannakopoulou, Sofia Tseleni, Dimitrios J. Stravopodis and Ema Anastasiadou

Int. J. Mol. Sci. 2020, 21(11), 4007; https://doi.org/10.3390/ijms21114007 - 3 Jun 2020

Cited by 9 | Viewed by 5573

Abstract

Regulation of gene expression has emerged as a fundamental element of transcript homeostasis. Key effectors in this process are the Argonautes (AGOs), highly specialized RNA-binding proteins (RBPs) that form complexes, such as the RNA-Induced Silencing Complex (RISC). AGOs dictate post-transcriptional gene-silencing by directly [...] Read more.

Regulation of gene expression has emerged as a fundamental element of transcript homeostasis. Key effectors in this process are the Argonautes (AGOs), highly specialized RNA-binding proteins (RBPs) that form complexes, such as the RNA-Induced Silencing Complex (RISC). AGOs dictate post-transcriptional gene-silencing by directly loading small RNAs and repressing their mRNA targets through small RNA-sequence complementarity. The four human highly-conserved family-members (AGO1, AGO2, AGO3, and AGO4) demonstrate multi-faceted and versatile roles in transcriptome’s stability, plasticity, and functionality. The post-translational modifications of AGOs in critical amino acid residues, the nucleotide polymorphisms and mutations, and the deregulation of expression and interactions are tightly associated with aberrant activities, which are observed in a wide spectrum of pathologies. Through constantly accumulating information, the AGOs’ fundamental engagement in multiple human diseases has recently emerged. The present review examines new insights into AGO-driven pathology and AGO-deregulation patterns in a variety of diseases such as in viral infections and propagations, autoimmune diseases, cancers, metabolic deficiencies, neuronal disorders, and human infertility. Altogether, AGO seems to be a crucial contributor to pathogenesis and its targeting may serve as a novel and powerful therapeutic tool for the successful management of diverse human diseases in the clinic. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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17 pages, 607 KiB

Open AccessReview

RNA-Binding Proteins in Pulmonary Hypertension

by Hui Zhang, R. Dale Brown, Kurt R. Stenmark and Cheng-Jun Hu

Int. J. Mol. Sci. 2020, 21(11), 3757; https://doi.org/10.3390/ijms21113757 - 26 May 2020

Cited by 6 | Viewed by 3468

Abstract

Pulmonary hypertension (PH) is a life-threatening disease characterized by significant vascular remodeling and aberrant expression of genes involved in inflammation, apoptosis resistance, proliferation, and metabolism. Effective therapeutic strategies are limited, as mechanisms underlying PH pathophysiology, especially abnormal expression of genes, remain unclear. Most [...] Read more.

Pulmonary hypertension (PH) is a life-threatening disease characterized by significant vascular remodeling and aberrant expression of genes involved in inflammation, apoptosis resistance, proliferation, and metabolism. Effective therapeutic strategies are limited, as mechanisms underlying PH pathophysiology, especially abnormal expression of genes, remain unclear. Most PH studies on gene expression have focused on gene transcription. However, post-transcriptional alterations have been shown to play a critical role in inflammation and metabolic changes in diseases such as cancer and systemic cardiovascular diseases. In these diseases, RNA-binding proteins (RBPs) have been recognized as important regulators of aberrant gene expression via post-transcriptional regulation; however, their role in PH is less clear. Identifying RBPs in PH is of great importance to better understand PH pathophysiology and to identify new targets for PH treatment. In this manuscript, we review the current knowledge on the role of dysregulated RBPs in abnormal mRNA gene expression as well as aberrant non-coding RNA processing and expression (e.g., miRNAs) in PH. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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29 pages, 2569 KiB

Open AccessReview

RNA-Binding Proteins in Acute Leukemias

by Konstantin Schuschel, Matthias Helwig, Stefan Hüttelmaier, Dirk Heckl, Jan-Henning Klusmann and Jessica I Hoell

Int. J. Mol. Sci. 2020, 21(10), 3409; https://doi.org/10.3390/ijms21103409 - 12 May 2020

Cited by 35 | Viewed by 7687

Abstract

Acute leukemias are genetic diseases caused by translocations or mutations, which dysregulate hematopoiesis towards malignant transformation. However, the molecular mode of action is highly versatile and ranges from direct transcriptional to post-transcriptional control, which includes RNA-binding proteins (RBPs) as crucial regulators of cell [...] Read more.

Acute leukemias are genetic diseases caused by translocations or mutations, which dysregulate hematopoiesis towards malignant transformation. However, the molecular mode of action is highly versatile and ranges from direct transcriptional to post-transcriptional control, which includes RNA-binding proteins (RBPs) as crucial regulators of cell fate. RBPs coordinate RNA dynamics, including subcellular localization, translational efficiency and metabolism, by binding to their target messenger RNAs (mRNAs), thereby controlling the expression of the encoded proteins. In view of the growing interest in these regulators, this review summarizes recent research regarding the most influential RBPs relevant in acute leukemias in particular. The reported RBPs, either dysregulated or as components of fusion proteins, are described with respect to their functional domains, the pathways they affect, and clinical aspects associated with their dysregulation or altered functions. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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29 pages, 1535 KiB

Open AccessReview

RNA-Targeted Therapies and High-Throughput Screening Methods

by Siran Zhu, Saul Rooney and Gracjan Michlewski

Int. J. Mol. Sci. 2020, 21(8), 2996; https://doi.org/10.3390/ijms21082996 - 23 Apr 2020

Cited by 19 | Viewed by 8253

Abstract

RNA-binding proteins (RBPs) are involved in regulating all aspects of RNA metabolism, including processing, transport, translation, and degradation. Dysregulation of RNA metabolism is linked to a plethora of diseases, such as cancer, neurodegenerative diseases, and neuromuscular disorders. Recent years have seen a dramatic [...] Read more.

RNA-binding proteins (RBPs) are involved in regulating all aspects of RNA metabolism, including processing, transport, translation, and degradation. Dysregulation of RNA metabolism is linked to a plethora of diseases, such as cancer, neurodegenerative diseases, and neuromuscular disorders. Recent years have seen a dramatic shift in the knowledge base, with RNA increasingly being recognised as an attractive target for precision medicine therapies. In this article, we are going to review current RNA-targeted therapies. Furthermore, we will scrutinise a range of drug discoveries targeting protein-RNA interactions. In particular, we will focus on the interplay between Lin28 and let-7, splicing regulatory proteins and survival motor neuron (SMN) pre-mRNA, as well as HuR, Musashi, proteins and their RNA targets. We will highlight the mechanisms RBPs utilise to modulate RNA metabolism and discuss current high-throughput screening strategies. This review provides evidence that we are entering a new era of RNA-targeted medicine. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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22 pages, 518 KiB

Open AccessReview

RNA-Binding Proteins as Important Regulators of Long Non-Coding RNAs in Cancer

by Katharina Jonas, George A. Calin and Martin Pichler

Int. J. Mol. Sci. 2020, 21(8), 2969; https://doi.org/10.3390/ijms21082969 - 23 Apr 2020

Cited by 90 | Viewed by 8035

Abstract

The majority of the genome is transcribed into pieces of non-(protein) coding RNA, among which long non-coding RNAs (lncRNAs) constitute a large group of particularly versatile molecules that govern basic cellular processes including transcription, splicing, RNA stability, and translation. The frequent deregulation of [...] Read more.

The majority of the genome is transcribed into pieces of non-(protein) coding RNA, among which long non-coding RNAs (lncRNAs) constitute a large group of particularly versatile molecules that govern basic cellular processes including transcription, splicing, RNA stability, and translation. The frequent deregulation of numerous lncRNAs in cancer is known to contribute to virtually all hallmarks of cancer. An important regulatory mechanism of lncRNAs is the post-transcriptional regulation mediated by RNA-binding proteins (RBPs). So far, however, only a small number of known cancer-associated lncRNAs have been found to be regulated by the interaction with RBPs like human antigen R (HuR), ARE/poly(U)-binding/degradation factor 1 (AUF1), insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and tristetraprolin (TTP). These RBPs regulate, by various means, two aspects in particular, namely the stability and the localization of lncRNAs. Importantly, these RBPs themselves are commonly deregulated in cancer and might thus play a major role in the deregulation of cancer-related lncRNAs. There are, however, still many open questions, for example regarding the context specificity of these regulatory mechanisms that, in part, is based on the synergistic or competitive interaction between different RBPs. There is also a lack of knowledge on how RBPs facilitate the transport of lncRNAs between different cellular compartments. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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16 pages, 2875 KiB

Open AccessArticle

Knockdown of Musashi RNA Binding Proteins Decreases Radioresistance but Enhances Cell Motility and Invasion in Triple-Negative Breast Cancer

by Fabian M. Troschel, Annemarie Minte, Yahia Mahmoud Ismail, Amr Kamal, Mahmoud Salah Abdullah, Sarah Hamdy Ahmed, Marie Deffner, Björn Kemper, Ludwig Kiesel, Hans Theodor Eich, Sherif Abdelaziz Ibrahim, Martin Götte and Burkhard Greve

Int. J. Mol. Sci. 2020, 21(6), 2169; https://doi.org/10.3390/ijms21062169 - 21 Mar 2020

Cited by 26 | Viewed by 5079

Abstract

The therapeutic potential of Musashi (MSI) RNA-binding proteins, important stemness-associated gene expression regulators, remains insufficiently understood in breast cancer. This study identifies the interplay between MSI protein expression, stem cell characteristics, radioresistance, cell invasiveness and migration. MSI-1, MSI-2 and Notch pathway elements were [...] Read more.

The therapeutic potential of Musashi (MSI) RNA-binding proteins, important stemness-associated gene expression regulators, remains insufficiently understood in breast cancer. This study identifies the interplay between MSI protein expression, stem cell characteristics, radioresistance, cell invasiveness and migration. MSI-1, MSI-2 and Notch pathway elements were investigated via quantitative polymerase chain reaction (qPCR) in 19 triple-negative breast cancer samples. Measurements were repeated in MDA-MB-231 cells after MSI-1 and -2 siRNA-mediated double knockdown, with further experiments performed after MSI silencing. Flow cytometry helped quantify expression of CD44 and leukemia inhibitory factor receptor (LIFR), changes in apoptosis and cell cycle progression. Proliferation and irradiation-induced effects were assessed using colony formation assays. Radiation-related proteins were investigated via Western blots. Finally, cell invasion assays and digital holographic microscopy for cell migration were performed. MSI proteins showed strong correlations with Notch pathway elements. MSI knockdown resulted in reduction of stem cell marker expression, cell cycle progression and proliferation, while increasing apoptosis. Cells were radiosensitized as radioresistance-conferring proteins were downregulated. However, MSI-silencing-mediated LIFR downregulation resulted in enhanced cell invasion and migration. We conclude that, while MSI knockdown results in several therapeutically desirable consequences, enhanced invasion and migration need to be counteracted before knockdown advantages can be fully exploited. Full article

(This article belongs to the Special Issue RNA-Binding Proteins in Human Diseases—from Mechanisms to Therapies)

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