International Journal of Molecular Sciences

Research

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Open AccessArticle

La Autoantigen Induces Ribosome Binding Protein 1 (RRBP1) Expression through Internal Ribosome Entry Site (IRES)-Mediated Translation during Cellular Stress Condition

by Wenqing Gao, Qi Li, Ruiyu Zhu and Jian Jin

Int. J. Mol. Sci. 2016, 17(7), 1174; https://doi.org/10.3390/ijms17071174 - 20 Jul 2016

Cited by 18 | Viewed by 6697

Abstract

The function of ribosome binding protein 1 (RRBP1) is regulating the transportation and secretion of some intracellular proteins in mammalian cells. Transcription of RRBP1 is induced by various cytokines. However, few studies focused on the process of RRPB1 mRNA translation. The RRBP1 mRNA [...] Read more.

The function of ribosome binding protein 1 (RRBP1) is regulating the transportation and secretion of some intracellular proteins in mammalian cells. Transcription of RRBP1 is induced by various cytokines. However, few studies focused on the process of RRPB1 mRNA translation. The RRBP1 mRNA has a long 5′ untranslated region that potentially formed a stable secondary structure. In this study, we show that the 5′ UTR of RRBP1 mRNA contains an internal ribosome entry site (IRES). Moreover, the RRBP1 expression is induced by chemotherapeutic drug paclitaxel or adriamycin in human hepatocellular carcinoma cells and accompanied with the increased expression of La autoantigen (La), which binds to RRBP1 IRES element and facilitates translation initiation. Interestingly, we found IRES-mediated RRBP1 translation is also activated during serum-starvation condition which can induce cytoplasmic localization of La. After mapping the entire RRBP1 5′ UTR, we determine the core IRES activity is located between nt-237 and -58. Furthermore, two apical GARR loops within the functional RRBP1 IRES elements may be important for La binding. These results strongly suggest an important role for IRES-dependent translation of RRBP1 mRNA in hepatocellular carcinoma cells during cellular stress conditions. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Open AccessArticle

MyoD Is a Novel Activator of Porcine FIT1 Gene by Interacting with the Canonical E-Box Element during Myogenesis

by Chi Yan, Xiaoliang Xia, Junxian He, Zhuqing Ren, Dequan Xu, Yuanzhu Xiong and Bo Zuo

Int. J. Mol. Sci. 2015, 16(10), 25014-25030; https://doi.org/10.3390/ijms161025014 - 20 Oct 2015

Cited by 6 | Viewed by 5718

Abstract

Fat-induced transcript 1 (FIT1/FITM1) gene is a member of the conserved gene family important for triglyceride-rich lipid droplet accumulation. FIT1 gene displays a similar muscle-specific expression across pigs, mice, and humans. Thus pigs can act as a useful model of many human diseases [...] Read more.

Fat-induced transcript 1 (FIT1/FITM1) gene is a member of the conserved gene family important for triglyceride-rich lipid droplet accumulation. FIT1 gene displays a similar muscle-specific expression across pigs, mice, and humans. Thus pigs can act as a useful model of many human diseases resulting from misexpression of FIT1 gene. Triglyceride content in skeletal muscle plays a key role in pork meat quality and flavors. An insertion/deletion mutation in porcine FIT1 coding region shows a high correlation with a series of fat traits. To gain better knowledge of the potential role of FIT1 gene in human diseases and the correlations with pork meat quality, our attention is given to the region upstream of the porcine FIT1 coding sequence. We cloned ~1 kb of the 5′-flanking region of porcine FIT1 gene to define the role of this sequence in modulating the myogenic expression. A canonical E-box element that activated porcine FIT1 promoter activity during myogenesis was identified. Further analysis demonstrated that promoter activity was induced by overexpression of MyoD1, which bound to this canonical E-box during C2C12 differentiation. This is the first evidence that FIT1 as the direct novel target of MyoD is involved in muscle development. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Open AccessArticle

MicroRNA-16 Modulates HuR Regulation of Cyclin E1 in Breast Cancer Cells

by Xun Guo, Melanie C. Connick, Jennifer Vanderhoof, Mohammad-Ali Ishak and Rebecca S. Hartley

Int. J. Mol. Sci. 2015, 16(4), 7112-7132; https://doi.org/10.3390/ijms16047112 - 30 Mar 2015

Cited by 40 | Viewed by 7278

Abstract

RNA binding protein (RBPs) and microRNAs (miRNAs or miRs) are post-transcriptional regulators of gene expression that are implicated in development of cancers. Although their individual roles have been studied, the crosstalk between RBPs and miRNAs is under intense investigation. Here, we show that [...] Read more.

RNA binding protein (RBPs) and microRNAs (miRNAs or miRs) are post-transcriptional regulators of gene expression that are implicated in development of cancers. Although their individual roles have been studied, the crosstalk between RBPs and miRNAs is under intense investigation. Here, we show that in breast cancer cells, cyclin E1 upregulation by the RBP HuR is through specific binding to regions in the cyclin E1 mRNA 3' untranslated region (3'UTR) containing U-rich elements. Similarly, miR-16 represses cyclin E1, dependent on its cognate binding sites in the cyclin E1 3'UTR. Evidence in the literature indicates that HuR can regulate miRNA expression and recruit or dissociate RNA-induced silencing complexes (RISC). Despite this, miR-16 and HuR do not affect the other’s expression level or binding to the cyclin E1 3'UTR. While HuR overexpression partially blocks miR-16 repression of a reporter mRNA containing the cyclin E1 3'UTR, it does not block miR-16 repression of endogenous cyclin E1 mRNA. In contrast, miR-16 blocks HuR-mediated upregulation of cyclin E1. Overall our results suggest that miR-16 can override HuR upregulation of cyclin E1 without affecting HuR expression or association with the cyclin E1 mRNA. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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562 KiB

Open AccessArticle

HuR-Regulated mRNAs Associated with Nuclear hnRNP A1-RNP Complexes

by Olga Papadodima, Aristotelis Chatziioannou, Meropi Patrinou-Georgoula, Fragiskos N. Kolisis, Vasiliki Pletsa and Apostolia Guialis

Int. J. Mol. Sci. 2013, 14(10), 20256-20281; https://doi.org/10.3390/ijms141020256 - 11 Oct 2013

Cited by 3 | Viewed by 8734

Abstract

Post-transcriptional regulatory networks are dependent on the interplay of many RNA-binding proteins having a major role in mRNA processing events in mammals. We have been interested in the concerted action of the two RNA-binding proteins hnRNP A1 and HuR, both stable components of [...] Read more.

Post-transcriptional regulatory networks are dependent on the interplay of many RNA-binding proteins having a major role in mRNA processing events in mammals. We have been interested in the concerted action of the two RNA-binding proteins hnRNP A1 and HuR, both stable components of immunoselected hnRNP complexes and having a major nuclear localization. Specifically, we present here the application of the RNA-immunoprecipitation (RIP)-Chip technology to identify a population of nuclear transcripts associated with hnRNP A1-RNPs as isolated from the nuclear extract of either HuR WT or HuR-depleted (KO) mouse embryonic fibroblast (MEF) cells. The outcome of this analysis was a list of target genes regulated via HuR for their association (either increased or reduced) with the nuclear hnRNP A1-RNP complexes. Real time PCR analysis was applied to validate a selected number of nuclear mRNA transcripts, as well as to identify pre-spliced transcripts (in addition to their mature mRNA counterpart) within the isolated nuclear hnRNP A1-RNPs. The differentially enriched mRNAs were found to belong to GO categories relevant to biological processes anticipated for hnRNP A1 and HuR (such as transport, transcription, translation, apoptosis and cell cycle) indicating their concerted function in mRNA metabolism. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Open AccessArticle

Celf1 Is Required for Formation of Endoderm-Derived Organs in Zebrafish

by Naoyuki Tahara, Yasumasa Bessho and Takaaki Matsui

Int. J. Mol. Sci. 2013, 14(9), 18009-18023; https://doi.org/10.3390/ijms140918009 - 3 Sep 2013

Cited by 7 | Viewed by 8515

Abstract

We recently reported that an RNA binding protein called Cugbp Elav-like family member 1 (Celf1) regulates somite symmetry and left-right patterning in zebrafish. In this report, we show additional roles of Celf1 in zebrafish organogenesis. When celf1 is knocked down by using an [...] Read more.

We recently reported that an RNA binding protein called Cugbp Elav-like family member 1 (Celf1) regulates somite symmetry and left-right patterning in zebrafish. In this report, we show additional roles of Celf1 in zebrafish organogenesis. When celf1 is knocked down by using an antisense morpholino oligonucleotides (MO), liver buds fail to form, and pancreas buds do not form a cluster, suggesting earlier defects in endoderm organogenesis. As expected, we found failures in endoderm cell growth and migration during gastrulation in embryos injected with celf1-MOs. RNA immunoprecipitation revealed that Celf1 binds to gata5 and cdc42 mRNAs which are known to be involved in cell growth and migration, respectively. Our results therefore suggest that Celf1 regulates proper organogenesis of endoderm-derived tissues by regulating the expression of such targets. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Review

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1279 KiB

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LARP6 Meets Collagen mRNA: Specific Regulation of Type I Collagen Expression

by Yujie Zhang and Branko Stefanovic

Int. J. Mol. Sci. 2016, 17(3), 419; https://doi.org/10.3390/ijms17030419 - 22 Mar 2016

Cited by 62 | Viewed by 9509

Abstract

Type I collagen is the most abundant structural protein in all vertebrates, but its constitutive rate of synthesis is low due to long half-life of the protein (60–70 days). However, several hundred fold increased production of type I collagen is often seen in [...] Read more.

Type I collagen is the most abundant structural protein in all vertebrates, but its constitutive rate of synthesis is low due to long half-life of the protein (60–70 days). However, several hundred fold increased production of type I collagen is often seen in reparative or reactive fibrosis. The mechanism which is responsible for this dramatic upregulation is complex, including multiple levels of regulation. However, posttranscriptional regulation evidently plays a predominant role. Posttranscriptional regulation comprises processing, transport, stabilization and translation of mRNAs and is executed by RNA binding proteins. There are about 800 RNA binding proteins, but only one, La ribonucleoprotein domain family member 6 (LARP6), is specifically involved in type I collagen regulation. In the 5′untranslated region (5’UTR) of mRNAs encoding for type I and type III collagens there is an evolutionally conserved stem-loop (SL) structure; this structure is not found in any other mRNA, including any other collagen mRNA. LARP6 binds to the 5′SL in sequence specific manner to regulate stability of collagen mRNAs and their translatability. Here, we will review current understanding of how is LARP6 involved in posttranscriptional regulation of collagen mRNAs. We will also discuss how other proteins recruited by LARP6, including nonmuscle myosin, vimentin, serine threonine kinase receptor associated protein (STRAP), 25 kD FK506 binding protein (FKBP25) and RNA helicase A (RHA), contribute to this process. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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RNA Binding Proteins in the miRNA Pathway

by Patrick Connerty, Alireza Ahadi and Gyorgy Hutvagner

Int. J. Mol. Sci. 2016, 17(1), 31; https://doi.org/10.3390/ijms17010031 - 26 Dec 2015

Cited by 67 | Viewed by 12141

Abstract

microRNAs (miRNAs) are short ~22 nucleotides (nt) ribonucleic acids which post-transcriptionally regulate gene expression. miRNAs are key regulators of all cellular processes, and the correct expression of miRNAs in an organism is crucial for proper development and cellular function. As a result, the [...] Read more.

microRNAs (miRNAs) are short ~22 nucleotides (nt) ribonucleic acids which post-transcriptionally regulate gene expression. miRNAs are key regulators of all cellular processes, and the correct expression of miRNAs in an organism is crucial for proper development and cellular function. As a result, the miRNA biogenesis pathway is highly regulated. In this review, we outline the basic steps of miRNA biogenesis and miRNA mediated gene regulation focusing on the role of RNA binding proteins (RBPs). We also describe multiple mechanisms that regulate the canonical miRNA pathway, which depends on a wide range of RBPs. Moreover, we hypothesise that the interaction between miRNA regulation and RBPs is potentially more widespread based on the analysis of available high-throughput datasets. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Open AccessReview

The Role of Alternative Splicing in the Control of Immune Homeostasis and Cellular Differentiation

by Mehmet Yabas, Hannah Elliott and Gerard F. Hoyne

Int. J. Mol. Sci. 2016, 17(1), 3; https://doi.org/10.3390/ijms17010003 - 22 Dec 2015

Cited by 60 | Viewed by 9065

Abstract

Alternative splicing of pre-mRNA helps to enhance the genetic diversity within mammalian cells by increasing the number of protein isoforms that can be generated from one gene product. This provides a great deal of flexibility to the host cell to alter protein function, [...] Read more.

Alternative splicing of pre-mRNA helps to enhance the genetic diversity within mammalian cells by increasing the number of protein isoforms that can be generated from one gene product. This provides a great deal of flexibility to the host cell to alter protein function, but when dysregulation in splicing occurs this can have important impact on health and disease. Alternative splicing is widely used in the mammalian immune system to control the development and function of antigen specific lymphocytes. In this review we will examine the splicing of pre-mRNAs yielding key proteins in the immune system that regulate apoptosis, lymphocyte differentiation, activation and homeostasis, and discuss how defects in splicing can contribute to diseases. We will describe how disruption to trans-acting factors, such as heterogeneous nuclear ribonucleoproteins (hnRNPs), can impact on cell survival and differentiation in the immune system. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Impacts of Alternative Splicing Events on the Differentiation of Adipocytes

by Jung-Chun Lin

Int. J. Mol. Sci. 2015, 16(9), 22169-22189; https://doi.org/10.3390/ijms160922169 - 14 Sep 2015

Cited by 21 | Viewed by 7419

Abstract

Alternative splicing was found to be a common phenomenon after the advent of whole transcriptome analyses or next generation sequencing. Over 90% of human genes were demonstrated to undergo at least one alternative splicing event. Alternative splicing is an effective mechanism to spatiotemporally [...] Read more.

Alternative splicing was found to be a common phenomenon after the advent of whole transcriptome analyses or next generation sequencing. Over 90% of human genes were demonstrated to undergo at least one alternative splicing event. Alternative splicing is an effective mechanism to spatiotemporally expand protein diversity, which influences the cell fate and tissue development. The first focus of this review is to highlight recent studies, which demonstrated effects of alternative splicing on the differentiation of adipocytes. Moreover, use of evolving high-throughput approaches, such as transcriptome analyses (RNA sequencing), to profile adipogenic transcriptomes, is also addressed. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Open AccessReview

RNA Recognition and Stress Granule Formation by TIA Proteins

by Saboora Waris, Matthew Charles James Wilce and Jacqueline Anne Wilce

Int. J. Mol. Sci. 2014, 15(12), 23377-23388; https://doi.org/10.3390/ijms151223377 - 16 Dec 2014

Cited by 60 | Viewed by 12226

Abstract

Stress granule (SG) formation is a primary mechanism through which gene expression is rapidly modulated when the eukaryotic cell undergoes cellular stresses (including heat, oxidative, viral infection, starvation). In particular, the sequestration of specifically targeted translationally stalled mRNAs into SGs limits the expression [...] Read more.

Stress granule (SG) formation is a primary mechanism through which gene expression is rapidly modulated when the eukaryotic cell undergoes cellular stresses (including heat, oxidative, viral infection, starvation). In particular, the sequestration of specifically targeted translationally stalled mRNAs into SGs limits the expression of a subset of genes, but allows the expression of heatshock proteins that have a protective effect in the cell. The importance of SGs is seen in several disease states in which SG function is disrupted. Fundamental to SG formation are the T cell restricted intracellular antigen (TIA) proteins (TIA-1 and TIA-1 related protein (TIAR)), that both directly bind to target RNA and self-associate to seed the formation of SGs. Here a summary is provided of the current understanding of the way in which TIA proteins target specific mRNA, and how TIA self-association is triggered under conditions of cellular stress. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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High-Resolution Imaging Reveals New Features of Nuclear Export of mRNA through the Nuclear Pore Complexes

by Joseph M. Kelich and Weidong Yang

Int. J. Mol. Sci. 2014, 15(8), 14492-14504; https://doi.org/10.3390/ijms150814492 - 20 Aug 2014

Cited by 7 | Viewed by 10062

Abstract

The nuclear envelope (NE) of eukaryotic cells provides a physical barrier for messenger RNA (mRNA) and the associated proteins (mRNPs) traveling from sites of transcription in the nucleus to locations of translation processing in the cytoplasm. Nuclear pore complexes (NPCs) embedded in the [...] Read more.

The nuclear envelope (NE) of eukaryotic cells provides a physical barrier for messenger RNA (mRNA) and the associated proteins (mRNPs) traveling from sites of transcription in the nucleus to locations of translation processing in the cytoplasm. Nuclear pore complexes (NPCs) embedded in the NE serve as a dominant gateway for nuclear export of mRNA. However, the fundamental characterization of export dynamics of mRNPs through the NPC has been hindered by several technical limits. First, the size of NPC that is barely below the diffraction limit of conventional light microscopy requires a super-resolution microscopy imaging approach. Next, the fast transit of mRNPs through the NPC further demands a high temporal resolution by the imaging approach. Finally, the inherent three-dimensional (3D) movements of mRNPs through the NPC demand the method to provide a 3D mapping of both transport kinetics and transport pathways of mRNPs. This review will highlight the recently developed super-resolution imaging techniques advanced from 1D to 3D for nuclear export of mRNPs and summarize the new features in the dynamic nuclear export process of mRNPs revealed from these technical advances. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Open AccessReview

Role of Sam68 in Post-Transcriptional Gene Regulation

by Flora Sánchez-Jiménez and Víctor Sánchez-Margalet

Int. J. Mol. Sci. 2013, 14(12), 23402-23419; https://doi.org/10.3390/ijms141223402 - 28 Nov 2013

Cited by 45 | Viewed by 8851

Abstract

The STAR family of proteins links signaling pathways to various aspects of post-transcriptional regulation and processing of RNAs. Sam68 belongs to this class of heteronuclear ribonucleoprotein particle K (hnRNP K) homology (KH) single domain-containing family of RNA-binding proteins that also contains some domains [...] Read more.

The STAR family of proteins links signaling pathways to various aspects of post-transcriptional regulation and processing of RNAs. Sam68 belongs to this class of heteronuclear ribonucleoprotein particle K (hnRNP K) homology (KH) single domain-containing family of RNA-binding proteins that also contains some domains predicted to bind critical components in signal transduction pathways. In response to phosphorylation and other post-transcriptional modifications, Sam68 has been shown to have the ability to link signal transduction pathways to downstream effects regulating RNA metabolism, including transcription, alternative splicing or RNA transport. In addition to its function as a docking protein in some signaling pathways, this prototypic STAR protein has been identified to have a nuclear localization and to take part in the formation of both nuclear and cytosolic multi-molecular complexes such as Sam68 nuclear bodies and stress granules. Coupling with other proteins and RNA targets, Sam68 may play a role in the regulation of differential expression and mRNA processing and translation according to internal and external signals, thus mediating important physiological functions, such as cell death, proliferation or cell differentiation. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Open AccessReview

New Insights into Functional Roles of the Polypyrimidine Tract-Binding Protein

by Maria Grazia Romanelli, Erica Diani and Patricia Marie-Jeanne Lievens

Int. J. Mol. Sci. 2013, 14(11), 22906-22932; https://doi.org/10.3390/ijms141122906 - 20 Nov 2013

Cited by 94 | Viewed by 15093

Abstract

Polypyrimidine Tract Binding Protein (PTB) is an intensely studied RNA binding protein involved in several post-transcriptional regulatory events of gene expression. Initially described as a pre-mRNA splicing regulator, PTB is now widely accepted as a multifunctional protein shuttling between nucleus and cytoplasm. Accordingly, [...] Read more.

Polypyrimidine Tract Binding Protein (PTB) is an intensely studied RNA binding protein involved in several post-transcriptional regulatory events of gene expression. Initially described as a pre-mRNA splicing regulator, PTB is now widely accepted as a multifunctional protein shuttling between nucleus and cytoplasm. Accordingly, PTB can interact with selected RNA targets, structural elements and proteins. There is increasing evidence that PTB and its paralog PTBP2 play a major role as repressors of alternatively spliced exons, whose transcription is tissue-regulated. In addition to alternative splicing, PTB is involved in almost all steps of mRNA metabolism, including polyadenylation, mRNA stability and initiation of protein translation. Furthermore, it is well established that PTB recruitment in internal ribosome entry site (IRES) activates the translation of picornaviral and cellular proteins. Detailed studies of the structural properties of PTB have contributed to our understanding of the mechanism of RNA binding by RNA Recognition Motif (RRM) domains. In the present review, we will describe the structural properties of PTB, its paralogs and co-factors, the role in post-transcriptional regulation and actions in cell differentiation and pathogenesis. Defining the multifunctional roles of PTB will contribute to the understanding of key regulatory events in gene expression. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Open AccessReview

The Ribonucleoprotein Csr Network

by Ethel Seyll and Laurence Van Melderen

Int. J. Mol. Sci. 2013, 14(11), 22117-22131; https://doi.org/10.3390/ijms141122117 - 8 Nov 2013

Cited by 17 | Viewed by 8187

Abstract

Ribonucleoprotein complexes are essential regulatory components in bacteria. In this review, we focus on the carbon storage regulator (Csr) network, which is well conserved in the bacterial world. This regulatory network is composed of the CsrA master regulator, its targets and regulators. CsrA [...] Read more.

Ribonucleoprotein complexes are essential regulatory components in bacteria. In this review, we focus on the carbon storage regulator (Csr) network, which is well conserved in the bacterial world. This regulatory network is composed of the CsrA master regulator, its targets and regulators. CsrA binds to mRNA targets and regulates translation either negatively or positively. Binding to small non-coding RNAs controls activity of this protein. Expression of these regulators is tightly regulated at the level of transcription and stability by various global regulators (RNAses, two-component systems, alarmone). We discuss the implications of these complex regulations in bacterial adaptation. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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RNA-Binding Proteins Impacting on Internal Initiation of Translation

by Encarnación Martínez-Salas, Gloria Lozano, Javier Fernandez-Chamorro, Rosario Francisco-Velilla, Alfonso Galan and Rosa Diaz

Int. J. Mol. Sci. 2013, 14(11), 21705-21726; https://doi.org/10.3390/ijms141121705 - 1 Nov 2013

Cited by 52 | Viewed by 12816

Abstract

RNA-binding proteins (RBPs) are pivotal regulators of all the steps of gene expression. RBPs govern gene regulation at the post-transcriptional level by virtue of their capacity to assemble ribonucleoprotein complexes on certain RNA structural elements, both in normal cells and in response to [...] Read more.

RNA-binding proteins (RBPs) are pivotal regulators of all the steps of gene expression. RBPs govern gene regulation at the post-transcriptional level by virtue of their capacity to assemble ribonucleoprotein complexes on certain RNA structural elements, both in normal cells and in response to various environmental stresses. A rapid cellular response to stress conditions is triggered at the step of translation initiation. Two basic mechanisms govern translation initiation in eukaryotic mRNAs, the cap-dependent initiation mechanism that operates in most mRNAs, and the internal ribosome entry site (IRES)-dependent mechanism activated under conditions that compromise the general translation pathway. IRES elements are cis-acting RNA sequences that recruit the translation machinery using a cap-independent mechanism often assisted by a subset of translation initiation factors and various RBPs. IRES-dependent initiation appears to use different strategies to recruit the translation machinery depending on the RNA organization of the region and the network of RBPs interacting with the element. In this review we discuss recent advances in understanding the implications of RBPs on IRES-dependent translation initiation. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Open AccessReview

Disease Animal Models of TDP-43 Proteinopathy and Their Pre-Clinical Applications

by Yu-Chih Liu, Po-Min Chiang and Kuen-Jer Tsai

Int. J. Mol. Sci. 2013, 14(10), 20079-20111; https://doi.org/10.3390/ijms141020079 - 9 Oct 2013

Cited by 33 | Viewed by 12673

Abstract

Frontotemperal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are two common neurodegenerative diseases. TDP-43 is considered to be a major disease protein in FTLD/ALS, but it’s exact role in the pathogenesis and the effective treatments remains unknown. To address this question and [...] Read more.

Frontotemperal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are two common neurodegenerative diseases. TDP-43 is considered to be a major disease protein in FTLD/ALS, but it’s exact role in the pathogenesis and the effective treatments remains unknown. To address this question and to determine a potential treatment for FTLD/ALS, the disease animal models of TDP-43 proteinopathy have been established. TDP-43 proteinopathy is the histologic feature of FTLD/ALS and is associated with disease progression. Studies on the disease animal models with TDP-43 proteinopathy and their pre-clinical applications are reviewed and summarized. Through these disease animal models, parts of TDP-43 functions in physiological and pathological conditions will be better understood and possible treatments for FTLD/ALS with TDP-43 proteinopathy may be identified for possible clinical applications in the future. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Posttranscriptional Regulation of Insulin Family Ligands and Receptors

by Amaresh C. Panda, Ioannis Grammatikakis, Je-Hyun Yoon and Kotb Abdelmohsen

Int. J. Mol. Sci. 2013, 14(9), 19202-19229; https://doi.org/10.3390/ijms140919202 - 18 Sep 2013

Cited by 19 | Viewed by 9828

Abstract

Insulin system including ligands (insulin and IGFs) and their shared receptors (IR and IGFR) are critical regulators of insulin signaling and glucose homeostasis. Altered insulin system is associated with major pathological conditions like diabetes and cancer. The mRNAs encoding for these ligands and [...] Read more.

Insulin system including ligands (insulin and IGFs) and their shared receptors (IR and IGFR) are critical regulators of insulin signaling and glucose homeostasis. Altered insulin system is associated with major pathological conditions like diabetes and cancer. The mRNAs encoding for these ligands and their receptors are posttranscriptionally controlled by three major groups of regulators; (i) alternative splicing regulatory factors; (ii) turnover and translation regulator RNA-binding proteins (TTR-RBPs); and (iii) non-coding RNAs including miRNAs and long non-coding RNAs (lncRNAs). In this review, we discuss the influence of these regulators on alternative splicing, mRNA stability and translation. Due to the pathological impacts of insulin system, we also discussed the possibilities of discovering new potential regulators which will improve understanding of insulin system and associated diseases. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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hnRNP A1: The Swiss Army Knife of Gene Expression

by Jacques Jean-Philippe, Sean Paz and Massimo Caputi

Int. J. Mol. Sci. 2013, 14(9), 18999-19024; https://doi.org/10.3390/ijms140918999 - 16 Sep 2013

Cited by 221 | Viewed by 18194

Abstract

Eukaryotic cells express a large variety of RNA binding proteins (RBPs), with diverse affinities and specificities towards target RNAs. These proteins play a crucial role in almost every aspect of RNA biogenesis, expression and function. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a complex [...] Read more.

Eukaryotic cells express a large variety of RNA binding proteins (RBPs), with diverse affinities and specificities towards target RNAs. These proteins play a crucial role in almost every aspect of RNA biogenesis, expression and function. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a complex and diverse family of RNA binding proteins. hnRNPs display multiple functions in the processing of heterogeneous nuclear RNAs into mature messenger RNAs. hnRNP A1 is one of the most abundant and ubiquitously expressed members of this protein family. hnRNP A1 plays multiple roles in gene expression by regulating major steps in the processing of nascent RNA transcripts. The transcription, splicing, stability, export through nuclear pores and translation of cellular and viral transcripts are all mechanisms modulated by this protein. The diverse functions played by hnRNP A1 are not limited to mRNA biogenesis, but extend to the processing of microRNAs, telomere maintenance and the regulation of transcription factor activity. Genomic approaches have recently uncovered the extent of hnRNP A1 roles in the development and differentiation of living organisms. The aim of this review is to highlight recent developments in the study of this protein and to describe its functions in cellular and viral gene expression and its role in human pathologies. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Post-Transcriptional Controls by Ribonucleoprotein Complexes in the Acquisition of Drug Resistance

by Hoin Kang, Chongtae Kim, Heejin Lee, Wook Kim and Eun Kyung Lee

Int. J. Mol. Sci. 2013, 14(8), 17204-17220; https://doi.org/10.3390/ijms140817204 - 20 Aug 2013

Cited by 19 | Viewed by 7897

Abstract

Acquisition of drug resistance leads to failure of anti-cancer treatments and therapies. Although several successive chemotherapies are available, along with efforts towards clinical applications of new anti-cancer drugs, it is generally realized that there is a long way to go to treat cancers. [...] Read more.

Acquisition of drug resistance leads to failure of anti-cancer treatments and therapies. Although several successive chemotherapies are available, along with efforts towards clinical applications of new anti-cancer drugs, it is generally realized that there is a long way to go to treat cancers. Resistance to anti-cancer drugs results from various factors, including genetic as well as epigenetic differences in tumors. Determining the molecular and cellular mechanisms responsible for the acquisition of drug resistance may be a helpful approach for the development of new therapeutic strategies to overcome treatment failure. Several studies have shown that the acquisition of drug resistance is tightly regulated by post-transcriptional regulators such as RNA binding proteins (RBPs) and microRNAs (miRNAs), which change the stability and translation of mRNAs encoding factors involved in cell survival, proliferation, epithelial-mesenchymal transition, and drug metabolism. Here, we review our current understanding of ribonucleoprotein complexes, including RBPs and miRNAs, which play critical roles in the acquisition of drug resistance and have potential clinical implications for cancer. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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NF90 in Posttranscriptional Gene Regulation and MicroRNA Biogenesis

by Kiyoshi Masuda, Yuki Kuwano, Kensei Nishida, Kazuhito Rokutan and Issei Imoto

Int. J. Mol. Sci. 2013, 14(8), 17111-17121; https://doi.org/10.3390/ijms140817111 - 19 Aug 2013

Cited by 37 | Viewed by 9374

Abstract

Gene expression patterns are effectively regulated by turnover and translation regulatory (TTR) RNA-binding proteins (RBPs). The TTR-RBPs control gene expression at posttranscriptional levels, such as pre-mRNA splicing, mRNA cytoplasmic export, turnover, storage, and translation. Double-stranded RNA binding proteins (DSRBPs) are known to regulate [...] Read more.

Gene expression patterns are effectively regulated by turnover and translation regulatory (TTR) RNA-binding proteins (RBPs). The TTR-RBPs control gene expression at posttranscriptional levels, such as pre-mRNA splicing, mRNA cytoplasmic export, turnover, storage, and translation. Double-stranded RNA binding proteins (DSRBPs) are known to regulate many processes of cellular metabolism, including transcriptional control, translational control, mRNA processing and localization. Nuclear factor 90 (NF90), one of the DSRBPs, is abundantly expressed in vertebrate tissue and participates in many aspects of RNA metabolism. NF90 was originally purified as a component of a DNA binding complex which binds to the antigen recognition response element 2 in the interleukin 2 promoter. Recent studies have provided us with interesting insights into its possible physiological roles in RNA metabolism, including transcription, degradation, and translation. In addition, it was shown that NF90 regulates microRNA expression. In this review, we try to focus on the function of NF90 in posttranscriptional gene regulation and microRNA biogenesis. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Open AccessReview

Post-Transcriptional Regulation by Poly(ADP-ribosyl)ation of the RNA-Binding Proteins

by Yingbiao Ji and Alexei V. Tulin

Int. J. Mol. Sci. 2013, 14(8), 16168-16183; https://doi.org/10.3390/ijms140816168 - 5 Aug 2013

Cited by 50 | Viewed by 10873

Abstract

Gene expression is intricately regulated at the post-transcriptional level by RNA-binding proteins (RBPs) via their interactions with pre-messenger RNA (pre-mRNA) and mRNA during development. However, very little is known about the mechanism regulating RBP activities in RNA metabolism. During the past few years, [...] Read more.

Gene expression is intricately regulated at the post-transcriptional level by RNA-binding proteins (RBPs) via their interactions with pre-messenger RNA (pre-mRNA) and mRNA during development. However, very little is known about the mechanism regulating RBP activities in RNA metabolism. During the past few years, a large body of evidence has suggested that many RBPs, such as heterogeneous nuclear ribonucleoproteins (hnRNPs), undergo post-translational modification through poly(ADP-ribosyl)ation to modulate RNA processing, including splicing, polyadenylation, translation, miRNA biogenesis and rRNA processing. Accordingly, RBP poly(ADP-ribosyl)ation has been shown to be involved in stress responses, stem cell differentiation and retinal morphogenesis. Here, we summarize recent advances in understanding the biological roles of RBP poly(ADP-ribosyl)ation, as controlled by Poly(ADP-ribose) Polymerases (PARPs) and Poly(ADP-ribose) Glycohydrolase (PARG). In addition, we discuss the potential of PARP and PARG inhibitors for the treatment of RBP-related human diseases, including cancer and neurodegenerative disorders. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Post-Transcriptional Regulation of Iron Homeostasis in Saccharomyces cerevisiae

by María Teresa Martínez-Pastor, Rosa De Llanos, Antonia María Romero and Sergi Puig

Int. J. Mol. Sci. 2013, 14(8), 15785-15809; https://doi.org/10.3390/ijms140815785 - 30 Jul 2013

Cited by 22 | Viewed by 10334

Abstract

Iron is an essential micronutrient for all eukaryotic organisms because it participates as a redox cofactor in a wide variety of biological processes. Recent studies in Saccharomyces cerevisiae have shown that in response to iron deficiency, an RNA-binding protein denoted Cth2 coordinates a [...] Read more.

Iron is an essential micronutrient for all eukaryotic organisms because it participates as a redox cofactor in a wide variety of biological processes. Recent studies in Saccharomyces cerevisiae have shown that in response to iron deficiency, an RNA-binding protein denoted Cth2 coordinates a global metabolic rearrangement that aims to optimize iron utilization. The Cth2 protein contains two Cx₈Cx₅Cx₃H tandem zinc fingers (TZFs) that specifically bind to adenosine/uridine-rich elements within the 3' untranslated region of many mRNAs to promote their degradation. The Cth2 protein shuttles between the nucleus and the cytoplasm. Once inside the nucleus, Cth2 binds target mRNAs and stimulates alternative 3' end processing. A Cth2/mRNA-containing complex is required for export to the cytoplasm, where the mRNA is degraded by the 5' to 3' degradation pathway. This post-transcriptional regulatory mechanism limits iron utilization in nonessential pathways and activates essential iron-dependent enzymes such as ribonucleotide reductase, which is required for DNA synthesis and repair. Recent findings indicate that the TZF-containing tristetraprolin protein also functions in modulating human iron homeostasis. Elevated iron concentrations can also be detrimental for cells. The Rnt1 RNase III exonuclease protects cells from excess iron by promoting the degradation of a subset of the Fe acquisition system when iron levels rise. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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398 KiB

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Ribonucleoprotein Complexes That Control Circadian Clocks

by Dongni Wang, Xiaodi Liang, Xianyun Chen and Jinhu Guo

Int. J. Mol. Sci. 2013, 14(5), 9018-9036; https://doi.org/10.3390/ijms14059018 - 25 Apr 2013

Cited by 13 | Viewed by 10783

Abstract

Circadian clocks are internal molecular time-keeping mechanisms that enable organisms to adjust their physiology and behavior to the daily surroundings. Misalignment of circadian clocks leads to both physiological and health impairment. Post-transcriptional regulation and translational regulation of circadian clocks have been extensively investigated. [...] Read more.

Circadian clocks are internal molecular time-keeping mechanisms that enable organisms to adjust their physiology and behavior to the daily surroundings. Misalignment of circadian clocks leads to both physiological and health impairment. Post-transcriptional regulation and translational regulation of circadian clocks have been extensively investigated. In addition, accumulating evidence has shed new light on the involvement of ribonucleoprotein complexes (RNPs) in the post-transcriptional regulation of circadian clocks. Numerous RNA-binding proteins (RBPs) and RNPs have been implicated in the post-transcriptional modification of circadian clock proteins in different model organisms. Herein, we summarize the advances in the current knowledge on the role of RNP complexes in circadian clock regulation. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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Open AccessTechnical Note

Nuclear and Cytoplasmic Soluble Proteins Extraction from a Small Quantity of Drosophila’s Whole Larvae and Tissues

by Luca Lo Piccolo, Rosa Bonaccorso and Maria Cristina Onorati

Int. J. Mol. Sci. 2015, 16(6), 12360-12367; https://doi.org/10.3390/ijms160612360 - 1 Jun 2015

Cited by 15 | Viewed by 8614

Abstract

The identification and study of protein’s function in several model organisms is carried out using both nuclear and cytoplasmic extracts. For a long time, Drosophila’s embryos have represented the main source for protein extractions, although in the last year, the importance of [...] Read more.

The identification and study of protein’s function in several model organisms is carried out using both nuclear and cytoplasmic extracts. For a long time, Drosophila’s embryos have represented the main source for protein extractions, although in the last year, the importance of collecting proteins extracts also from larval tissues has also been understood. Here we report a very simple protocol, improved by a previously developed method, to produce in a single extraction both highly stable nuclear and cytoplasmic protein extracts from a small quantity of whole Drosophila’s larvae or tissues, suitable for biochemical analyses like co-immunoprecipitation. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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