RNA-binding proteins and their role in the regulation of gene expression in Trypanosoma cruzi and Saccharomyces cerevisiae

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.

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The Tristetraprolin Family of RNA-Binding Proteins in Cancer: Progress and Future Prospects

Cancers ◽

10.3390/cancers12061539 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1539 ◽

Cited By ~ 2

Author(s):

Yogesh Saini ◽

Jian Chen ◽

Sonika Patial

Keyword(s):

Gene Expression ◽

Transcriptional Regulation ◽

Zinc Finger ◽

Binding Proteins ◽

Rna Binding ◽

Zinc Finger Protein ◽

Rna Binding Proteins ◽

Regulation Of Gene Expression ◽

Finger Protein ◽

Post Transcriptional Regulation

Post-transcriptional regulation of gene expression plays a key role in cellular proliferation, differentiation, migration, and apoptosis. Increasing evidence suggests dysregulated post-transcriptional gene expression as an important mechanism in the pathogenesis of cancer. The tristetraprolin family of RNA-binding proteins (RBPs), which include Zinc Finger Protein 36 (ZFP36; commonly referred to as tristetraprolin (TTP)), Zinc Finger Protein 36 like 1 (ZFP36L1), and Zinc Finger Protein 36 like 2 (ZFP36L2), play key roles in the post-transcriptional regulation of gene expression. Mechanistically, these proteins function by binding to the AU-rich elements within the 3′-untranslated regions of their target mRNAs and, in turn, increasing mRNA turnover. The TTP family RBPs are emerging as key regulators of multiple biological processes relevant to cancer and are aberrantly expressed in numerous human cancers. The TTP family RBPs have tumor-suppressive properties and are also associated with cancer prognosis, metastasis, and resistance to chemotherapy. Herein, we summarize the various hallmark molecular traits of cancers that are reported to be regulated by the TTP family RBPs. We emphasize the role of the TTP family RBPs in the regulation of trait-associated mRNA targets in relevant cancer types/cell lines. Finally, we highlight the potential of the TTP family RBPs as prognostic indicators and discuss the possibility of targeting these TTP family RBPs for therapeutic benefits.

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Selective Regulation of Gene Expression by Nuclear Factor 110, a Member of the NF90 Family of Double-stranded RNA-binding Proteins

Journal of Molecular Biology ◽

10.1016/s0022-2836(03)00885-4 ◽

2003 ◽

Vol 332 (1) ◽

pp. 85-98 ◽

Cited By ~ 42

Author(s):

Trevor W. Reichman ◽

Andrew M. Parrott ◽

Ivo Fierro-Monti ◽

David J. Caron ◽

Peter N. Kao ◽

...

Keyword(s):

Gene Expression ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Regulation Of Gene Expression ◽

Nuclear Factor ◽

Double Stranded Rna

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RNA-Binding Proteins in the Post-transcriptional Control of Skeletal Muscle Development, Regeneration and Disease

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.738978 ◽

2021 ◽

Vol 9 ◽

Author(s):

De-Li Shi ◽

Raphaëlle Grifone

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Binding Proteins ◽

Muscle Development ◽

Rna Binding ◽

Rna Binding Proteins ◽

Regulation Of Gene Expression ◽

The Body ◽

Skeletal Muscle Development ◽

Myogenic Program

Embryonic myogenesis is a temporally and spatially regulated process that generates skeletal muscle of the trunk and limbs. During this process, mononucleated myoblasts derived from myogenic progenitor cells within the somites undergo proliferation, migration and differentiation to elongate and fuse into multinucleated functional myofibers. Skeletal muscle is the most abundant tissue of the body and has the remarkable ability to self-repair by re-activating the myogenic program in muscle stem cells, known as satellite cells. Post-transcriptional regulation of gene expression mediated by RNA-binding proteins is critically required for muscle development during embryogenesis and for muscle homeostasis in the adult. Differential subcellular localization and activity of RNA-binding proteins orchestrates target gene expression at multiple levels to regulate different steps of myogenesis. Dysfunctions of these post-transcriptional regulators impair muscle development and homeostasis, but also cause defects in motor neurons or the neuromuscular junction, resulting in muscle degeneration and neuromuscular disease. Many RNA-binding proteins, such as members of the muscle blind-like (MBNL) and CUG-BP and ETR-3-like factors (CELF) families, display both overlapping and distinct targets in muscle cells. Thus they function either cooperatively or antagonistically to coordinate myoblast proliferation and differentiation. Evidence is accumulating that the dynamic interplay of their regulatory activity may control the progression of myogenic program as well as stem cell quiescence and activation. Moreover, the role of RNA-binding proteins that regulate post-transcriptional modification in the myogenic program is far less understood as compared with transcription factors involved in myogenic specification and differentiation. Here we review past achievements and recent advances in understanding the functions of RNA-binding proteins during skeletal muscle development, regeneration and disease, with the aim to identify the fundamental questions that are still open for further investigations.

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RNA Binding Proteins and its Regulation of Gene Expression

Journal of Applied Biological Chemistry ◽

10.3839/jabc.2015.032 ◽

2015 ◽

Vol 58 (3) ◽

pp. 201-208

Author(s):

Kyung Hee Roh ◽

Han-Chul Kang ◽

Jong-Bum Kim ◽

Hyun-UK Kim ◽

Kyung-Ryeol Lee ◽

...

Keyword(s):

Gene Expression ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Regulation Of Gene Expression

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RNA Binding Proteins and Gene Expression Regulation in Trypanosoma cruzi

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2020.00056 ◽

2020 ◽

Vol 10 ◽

Cited By ~ 2

Author(s):

Bruno A. A. Romagnoli ◽

Fabiola B. Holetz ◽

Lysangela R. Alves ◽

Samuel Goldenberg

Keyword(s):

Gene Expression ◽

Trypanosoma Cruzi ◽

Binding Proteins ◽

Rna Binding ◽

Gene Expression Regulation ◽

Rna Binding Proteins ◽

Expression Regulation

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Role of RNA-Binding Proteins in MAPK Signal Transduction Pathway

Journal of Signal Transduction ◽

10.1155/2011/109746 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 16

Author(s):

Reiko Sugiura ◽

Ryosuke Satoh ◽

Shunji Ishiwata ◽

Nanae Umeda ◽

Ayako Kita

Keyword(s):

Gene Expression ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Mapk Pathway ◽

Regulation Of Gene Expression ◽

Clinical Importance ◽

Mapk Signaling ◽

Present Evidence ◽

Target Mrnas

Mitogen-activated protein kinases (MAPKs), which are found in all eukaryotes, are signal transducing enzymes playing a central role in diverse biological processes, such as cell proliferation, sexual differentiation, and apoptosis. The MAPK signaling pathway plays a key role in the regulation of gene expression through the phosphorylation of transcription factors. Recent studies have identified several RNA-binding proteins (RBPs) as regulators of MAPK signaling because these RBPs bind to the mRNAs encoding the components of the MAPK pathway and regulate the stability of their transcripts. Moreover, RBPs also serve as targets of MAPKs because MAPK phosphorylate and regulate the ability of RBPs to bind and stabilize target mRNAs, thus controlling various cellular functions. In this review, we present evidence for the significance of the MAPK signaling in the regulation of RBPs and their target mRNAs, which provides additional information about the regulatory mechanism underlying gene expression. We further present evidence for the clinical importance of the posttranscriptional regulation of mRNA stability and its implications for drug discovery.

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Auto-regulatory feedback by RNA-binding proteins

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjz043 ◽

2019 ◽

Vol 11 (10) ◽

pp. 930-939 ◽

Cited By ~ 10

Author(s):

Michaela Müller-McNicoll ◽

Oliver Rossbach ◽

Jingyi Hui ◽

Jan Medenbach

Keyword(s):

Gene Expression ◽

Cell Fate ◽

Transcriptional Control ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Regulation Of Gene Expression ◽

Feedback Regulation ◽

Control Of Gene Expression ◽

Cell Fate Decisions

Abstract RNA-binding proteins (RBPs) are key regulators in post-transcriptional control of gene expression. Mutations that alter their activity or abundance have been implicated in numerous diseases such as neurodegenerative disorders and various types of cancer. This highlights the importance of RBP proteostasis and the necessity to tightly control the expression levels and activities of RBPs. In many cases, RBPs engage in an auto-regulatory feedback by directly binding to and influencing the fate of their own mRNAs, exerting control over their own expression. For this feedback control, RBPs employ a variety of mechanisms operating at all levels of post-transcriptional regulation of gene expression. Here we review RBP-mediated autogenous feedback regulation that either serves to maintain protein abundance within a physiological range (by negative feedback) or generates binary, genetic on/off switches important for e.g. cell fate decisions (by positive feedback).

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Characterization of the RNA-Binding Protein TcSgn1 in Trypanosoma cruzi

Microorganisms ◽

10.3390/microorganisms9050986 ◽

2021 ◽

Vol 9 (5) ◽

pp. 986

Author(s):

Camila Oliveira ◽

André P. Gerber ◽

Samuel Goldenberg ◽

Lysangela R. Alves

Keyword(s):

Gene Expression ◽

Trypanosoma Cruzi ◽

Rna Binding ◽

Rna Binding Proteins ◽

Binding Protein ◽

Regulation Of Gene Expression ◽

Rna Binding Protein ◽

Transcriptional Level ◽

Rna Recognition Motif ◽

Ribonucleoprotein Complexes

RNA-binding proteins (RBPs) participate in several steps of post-transcriptional regulation of gene expression, such as splicing, messenger RNA transport, mRNA localization, and translation. Gene-expression regulation in trypanosomatids occurs primarily at the post-transcriptional level, and RBPs play important roles in the process. Here, we characterized the RBP TcSgn1, which contains one RNA recognition motif (RRM). TcSgn1 is a close ortholog of yeast Saccharomyces cerevisiae protein ScSgn1, which plays a role in translational regulation in the cytoplasm. We found that TcSgn1 in Trypanosoma cruzi is localized in the nucleus in exponentially growing epimastigotes. By performing immunoprecipitation assays of TcSgn1, we identified hundreds of mRNAs associated with the protein, a significant fraction of them coding for nucleic acids binding, transcription, and endocytosis proteins. In addition, we show that TcSgn1 is capable of interacting directly with the poly(A) tail of the mRNAs. The study of parasites under nutritional stress showed that TcSgn1 was localized in cytoplasmic granules in addition to localizing in the nucleus. Similar to ScSgn1, we observed that TcSgn1 also interacts with the PABP1 protein, suggesting that this protein may play a role in regulating gene expression in T. cruzi. Taken together, our results show that RNA-binding protein TcSgn1 is part of ribonucleoprotein complexes associated with nuclear functions, stress response, and RNA metabolism.

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The Interplay of RNA Binding Proteins, Oxidative Stress and Mitochondrial Dysfunction in ALS

Antioxidants ◽

10.3390/antiox10040552 ◽

2021 ◽

Vol 10 (4) ◽

pp. 552

Author(s):

Jasmine Harley ◽

Benjamin E. Clarke ◽

Rickie Patani

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Mitochondrial Dysfunction ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Binding Protein ◽

Rna Binding Protein ◽

Therapeutic Strategies ◽

Lateral Sclerosis

RNA binding proteins fulfil a wide number of roles in gene expression. Multiple mechanisms of RNA binding protein dysregulation have been implicated in the pathomechanisms of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Oxidative stress and mitochondrial dysfunction also play important roles in these diseases. In this review, we highlight the mechanistic interplay between RNA binding protein dysregulation, oxidative stress and mitochondrial dysfunction in ALS. We also discuss different potential therapeutic strategies targeting these pathways.

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