Post-transcriptional and post-translational regulation of Bcl2

2010 ◽  
Vol 38 (6) ◽  
pp. 1571-1575 ◽  
Author(s):  
Shaun Willimott ◽  
Simon D. Wagner
Keyword(s):  
Translational Regulation ◽  
Transcriptional Control ◽  
Rna Binding ◽  
Constitutive Expression ◽  
Regulatory Elements ◽  
Therapeutic Approaches ◽  
Internal Ribosome Entry ◽  
Essential Function ◽  
Cellular Stresses ◽  
Bcl2 Expression

Bcl2 is an important pro-survival protein that has an essential function in normal immunity and whose constitutive expression leads to the development of lymphomas. Although transcriptional control of Bcl2 has been reported, increasing evidence suggests an important component of Bcl2 regulation is post-transcriptional. Phosphorylation of Bcl2 has been shown to enhance activity to allow response to extracellular growth-factor-mediated signals. Bcl2 mRNA contains regulatory elements in both its 5′- and 3′-UTRs (untranslated regions). An IRES (internal ribosome entry sequence) in the 5′-UTR permits continued translation in the presence of cellular stresses that reduce cap-dependent translation. The 3′-UTR of Bcl2 mRNA is 5.2 kb in length and contains multiple predicted miRNA (microRNA) and RNA-BP (RNA-binding protein)-binding sites. miR-15a and miR-16-1 have been found to inhibit Bcl2 expression in B-cells, whereas the RNA-BP nucleolin has been shown to increase Bcl2 expression by binding to the 3′-UTR and enhancing mRNA stability. Both decreased expression of miR-15a and miR-16-1 and increased nucleolin have been shown to be associated with increased Bcl2 expression and resistance to apoptosis in the common human disease, chronic lymphocytic leukaemia. miRNA-based therapeutic approaches to treat cancer are emerging. Bcl2 is highly regulated by miRNAs and is therefore an excellent candidate for such approaches.

scholarly journals PSI controls tim splicing and circadian period in Drosophila

2018 ◽  
Author(s):  
Lauren Foley ◽  
Jinli Ling ◽  
Radhika Joshi ◽  
Naveh Evantal ◽  
Sebastian Kadener ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Circadian Rhythms ◽  
Translational Regulation ◽  
Transcriptional Control ◽  
Rna Binding ◽  
P Element ◽  
Peripheral Tissues ◽  
Associated Proteins ◽  
Splicing Regulator ◽  
Post Transcriptional Regulation

AbstractThe Drosophila circadian pacemaker consists of transcriptional feedback loops subjected to both post-transcriptional and post-translational regulation. While post-translational regulatory mechanisms have been studied in detail, much less is known about circadian post-transcriptional control. To have a better understanding of the role and mechanisms of circadian post-transcriptional regulation, we targeted 364 RNA binding and RNA associated proteins with RNA interference. Among the 43 genes we identified was the alternative splicing regulator P-element somatic inhibitor (PSI). PSI downregulation shortens the period of circadian rhythms both in the brain and in peripheral tissues. Interestingly, we found that PSI regulates the thermosensitive alternative splicing of timeless (tim), promoting splicing events favored at warm temperature over those increased at cold temperature. Moreover, the period of circadian behavior was insensitive to PSI downregulation when flies could produce functional TIM proteins only from a transgene that cannot form the thermosensitive splicing isoforms. Therefore, we conclude that PSI regulates the period of Drosophila circadian rhythms through its modulation of the tim splicing pattern.

scholarly journals Deconstructing internal ribosome entry site elements: an update of structural motifs and functional divergences

Open Biology ◽  
2018 ◽  
Vol 8 (11) ◽  
pp. 180155 ◽  
Author(s):  
Gloria Lozano ◽  
Rosario Francisco-Velilla ◽  
Encarnacion Martinez-Salas
Keyword(s):  
Internal Ribosome Entry Site ◽  
Rna Structure ◽  
Rna Binding ◽  
Building Blocks ◽  
Regulatory Elements ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Ribonucleoprotein Complexes ◽  
Structure Conservation ◽  
Initiation Of Translation

Beyond the general cap-dependent translation initiation, eukaryotic organisms use alternative mechanisms to initiate protein synthesis. Internal ribosome entry site (IRES) elements are cis -acting RNA regions that promote internal initiation of translation using a cap-independent mechanism. However, their lack of primary sequence and secondary RNA structure conservation, as well as the diversity of host factor requirement to recruit the ribosomal subunits, suggest distinct types of IRES elements. In spite of this heterogeneity, conserved motifs preserve sequences impacting on RNA structure and RNA–protein interactions important for IRES-driven translation. This conservation brings the question of whether IRES elements could consist of basic building blocks, which upon evolutionary selection result in functional elements with different properties. Although RNA-binding proteins (RBPs) perform a crucial role in the assembly of ribonucleoprotein complexes, the versatility and plasticity of RNA molecules, together with their high flexibility and dynamism, determines formation of macromolecular complexes in response to different signals. These properties rely on the presence of short RNA motifs, which operate as modular entities, and suggest that decomposition of IRES elements in short modules could help to understand the different mechanisms driven by these regulatory elements. Here we will review evidence suggesting that model IRES elements consist of the combination of short modules, providing sites of interaction for ribosome subunits, eIFs and RBPs, with implications for definition of criteria to identify novel IRES-like elements genome wide.

scholarly journals An RNA-centric global view of Clostridioides difficile reveals broad activity of Hfq in a clinically important Gram-positive bacterium

2020 ◽  
Author(s):  
Manuela Fuchs ◽  
Vanessa Lamm-Schmidt ◽  
Falk Ponath ◽  
Laura Jenniches ◽  
Lars Barquist ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Rna Binding ◽  
Regulatory Elements ◽  
Infection Process ◽  
Positive Bacterium ◽  
Gram Positive ◽  
Target Mrnas ◽  
Clostridioides Difficile

ABSTRACTThe Gram-positive human pathogen Clostridioides difficile has emerged as the leading cause of antibiotic-associated diarrhea. Despite growing evidence for a role of Hfq in RNA-based gene regulation in C. difficile, little is known about the bacterium’s transcriptome architecture and mechanisms of post-transcriptional control. Here, we have applied a suite of RNA-centric techniques, including transcription start site mapping, transcription termination mapping and Hfq RIP-seq, to generate a single-nucleotide resolution RNA map of C. difficile 630. Our transcriptome annotation provides information about 5’ and 3’ untranslated regions, operon structures and non-coding regulators, including 42 sRNAs. These transcriptome data are accessible via an open-access browser called ‘Clost-Base’. Our results indicate functionality of many conserved riboswitches and predict novel cis-regulatory elements upstream of MDR-type ABC transporters and transcriptional regulators. Recent studies have revealed a role of sRNA-based regulation in several Gram-positive bacteria but their involvement with the RNA-binding protein Hfq remains controversial. Here, sequencing the RNA ligands of Hfq reveals in vivo association of many sRNAs along with hundreds of potential target mRNAs in C. difficile providing evidence for a global role of Hfq in post-transcriptional regulation in a Gram-positive bacterium. Through integration of Hfq-bound transcripts and computational approaches we predict regulated target mRNAs for the novel sRNA AtcS encoding several adhesins and the conserved oligopeptide transporter oppB that influences sporulation initiation in C. difficile. Overall, these findings provide a potential mechanistic explanation for increased biofilm formation and sporulation in an hfq deletion strain and lay the foundation for understanding clostridial ribo regulation with implications for the infection process.

scholarly journals Post-translational Control of RNA-Binding Proteins and Disease-Related Dysregulation

2021 ◽  
Vol 8 ◽  
Author(s):  
Alejandro Velázquez-Cruz ◽  
Blanca Baños-Jaime ◽  
Antonio Díaz-Quintana ◽  
Miguel A. De la Rosa ◽  
Irene Díaz-Moreno
Keyword(s):  
Translational Control ◽  
Translational Regulation ◽  
Transcriptional Control ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Physiological Role ◽  
Dynamic Composition ◽  
Mrna Metabolism ◽  
As Stress

Cell signaling mechanisms modulate gene expression in response to internal and external stimuli. Cellular adaptation requires a precise and coordinated regulation of the transcription and translation processes. The post-transcriptional control of mRNA metabolism is mediated by the so-called RNA-binding proteins (RBPs), which assemble with specific transcripts forming messenger ribonucleoprotein particles of highly dynamic composition. RBPs constitute a class of trans-acting regulatory proteins with affinity for certain consensus elements present in mRNA molecules. However, these regulators are subjected to post-translational modifications (PTMs) that constantly adjust their activity to maintain cell homeostasis. PTMs can dramatically change the subcellular localization, the binding affinity for RNA and protein partners, and the turnover rate of RBPs. Moreover, the ability of many RBPs to undergo phase transition and/or their recruitment to previously formed membrane-less organelles, such as stress granules, is also regulated by specific PTMs. Interestingly, the dysregulation of PTMs in RBPs has been associated with the pathophysiology of many different diseases. Abnormal PTM patterns can lead to the distortion of the physiological role of RBPs due to mislocalization, loss or gain of function, and/or accelerated or disrupted degradation. This Mini Review offers a broad overview of the post-translational regulation of selected RBPs and the involvement of their dysregulation in neurodegenerative disorders, cancer and other pathologies.

Sex determination in loggerhead turtles: differential expression of two hnRNP proteins

Development ◽  
1990 ◽  
Vol 109 (2) ◽  
pp. 305-312
Author(s):  
J.L. Harry ◽  
K.L. Williams ◽  
D.A. Briscoe
Keyword(s):  
Monoclonal Antibody ◽  
Sex Determination ◽  
Transcriptional Control ◽  
Rna Binding ◽  
Incubation Temperature ◽  
Constitutive Expression ◽  
Loggerhead Turtle ◽  
Differentially Expressed ◽  
Heat Shock Gene ◽  
Hnrnp Proteins

Sex determination in the loggerhead turtle, Caretta caretta, is controlled by incubation temperature during a critical period of embryogenesis. As heat-shock gene expression is temperature-dependent and has been shown to be associated with early developmental regulation in several organisms, we studied the constitutive expression of hsp70 and hsp90 in embryonic brain and urinogenital tissues to see if these proteins are differentially expressed during the sex-determining period in embryos incubated at male- (26 degrees C) and female- (32 degrees C) determining temperatures. The level of expression of hsp70 and hsp90, as determined from monoclonal antibody staining, is similar in both sexes during the sex-determining period. However, AC88, a monoclonal antibody that identifies hsp90 in several systems, recognised two additional protein bands (Mr 42 and 46 × 10(3)), which are differentially expressed in the urinogenital tissue of developing male and female embryos during the sex-determining period. While the 42K and 46K proteins appear in the urinogenital tissue of developing female (32 degrees C) embryos until stage 25, they are not expressed in the male (26 degrees C) urinogenital system after stage 24. Subsequent experiments have identified both turtle proteins as heterogeneous nuclear ribonucleoprotein particles (hnRNPs). As several hnRNP proteins have specific RNA-binding sites and are involved in mRNA processing reactions, the 46K protein may mediate post-transcriptional control of specific RNA transcripts required for sexual differentiation in C. caretta.

scholarly journals Drosophila PSI controls circadian period and the phase of circadian behavior under temperature cycle via tim splicing

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Lauren E Foley ◽  
Jinli Ling ◽  
Radhika Joshi ◽  
Naveh Evantal ◽  
Sebastian Kadener ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Circadian Rhythms ◽  
Translational Regulation ◽  
Transcriptional Control ◽  
Rna Binding ◽  
Temperature Cycling ◽  
P Element ◽  
Temperature Cycle ◽  
Associated Proteins ◽  
Circadian Behavior

The Drosophila circadian pacemaker consists of transcriptional feedback loops subjected to post-transcriptional and post-translational regulation. While post-translational regulatory mechanisms have been studied in detail, much less is known about circadian post-transcriptional control. Thus, we targeted 364 RNA binding and RNA associated proteins with RNA interference. Among the 43 hits we identified was the alternative splicing regulator P-element somatic inhibitor (PSI). PSI regulates the thermosensitive alternative splicing of timeless (tim), promoting splicing events favored at warm temperature over those increased at cold temperature. Psi downregulation shortens the period of circadian rhythms and advances the phase of circadian behavior under temperature cycle. Interestingly, both phenotypes were suppressed in flies that could produce TIM proteins only from a transgene that cannot form the thermosensitive splicing isoforms. Therefore, we conclude that PSI regulates the period of Drosophila circadian rhythms and circadian behavior phase during temperature cycling through its modulation of the tim splicing pattern.

scholarly journals Circular RNAs: Potential Applications as Therapeutic Targets and Biomarkers in Breast Cancer

2021 ◽  
Vol 7 (1) ◽  
pp. 2
Author(s):  
Debina Sarkar ◽  
Sarah D. Diermeier
Keyword(s):  
Breast Cancer ◽  
Translational Regulation ◽  
Closed Loop ◽  
Mechanisms Of Action ◽  
Circular Rnas ◽  
Therapeutic Approaches ◽  
Mirna Sponge ◽  
Bodily Fluids ◽  
Potential Applications ◽  
Non Coding Rnas

Circular RNAs (circRNAs) are a class of non-coding RNAs that form a covalently closed loop. A number of functions and mechanisms of action for circRNAs have been reported, including as miRNA sponge, exerting transcriptional and translational regulation, interacting with proteins, and coding for peptides. CircRNA dysregulation has also been implicated in many cancers, such as breast cancer. Their relatively high stability and presence in bodily fluids makes cancer-associated circRNAs promising candidates as a new biomarker. In this review, we summarize the research undertaken on circRNAs associated with breast cancer, discuss circRNAs as biomarkers, and present circRNA-based therapeutic approaches.

A Global Vista of the Epigenomic State of the Mouse Submandibular Gland

2021 ◽  
pp. 002203452110120
Author(s):  
C. Gluck ◽  
S. Min ◽  
A. Oyelakin ◽  
M. Che ◽  
E. Horeth ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Control ◽  
Expression Patterns ◽  
Global Gene Expression ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Submandibular Salivary Gland ◽  
Data Sets ◽  
Control Mechanisms ◽  
Chromatin Immunoprecipitation Sequencing

The parotid, submandibular, and sublingual glands represent a trio of oral secretory glands whose primary function is to produce saliva, facilitate digestion of food, provide protection against microbes, and maintain oral health. While recent studies have begun to shed light on the global gene expression patterns and profiles of salivary glands, particularly those of mice, relatively little is known about the location and identity of transcriptional control elements. Here we have established the epigenomic landscape of the mouse submandibular salivary gland (SMG) by performing chromatin immunoprecipitation sequencing experiments for 4 key histone marks. Our analysis of the comprehensive SMG data sets and comparisons with those from other adult organs have identified critical enhancers and super-enhancers of the mouse SMG. By further integrating these findings with complementary RNA-sequencing based gene expression data, we have unearthed a number of molecular regulators such as members of the Fox family of transcription factors that are enriched and likely to be functionally relevant for SMG biology. Overall, our studies provide a powerful atlas of cis-regulatory elements that can be leveraged for better understanding the transcriptional control mechanisms of the mouse SMG, discovery of novel genetic switches, and modulating tissue-specific gene expression in a targeted fashion.

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