Sleep-wake cycles drive daily dynamics of synaptic phosphorylation

The circadian clock drives daily changes of physiology, including sleep-wake cycles, through regulation of transcription, protein abundance, and function. Circadian phosphorylation controls cellular processes in peripheral organs, but little is known about its role in brain function and synaptic activity. We applied advanced quantitative phosphoproteomics to mouse forebrain synaptoneurosomes isolated across 24 hours, accurately quantifying almost 8000 phosphopeptides. Half of the synaptic phosphoproteins, including numerous kinases, had large-amplitude rhythms peaking at rest-activity and activity-rest transitions. Bioinformatic analyses revealed global temporal control of synaptic function through phosphorylation, including synaptic transmission, cytoskeleton reorganization, and excitatory/inhibitory balance. Sleep deprivation abolished 98% of all phosphorylation cycles in synaptoneurosomes, indicating that sleep-wake cycles rather than circadian signals are main drivers of synaptic phosphorylation, responding to both sleep and wake pressures.

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The Complexity of DEK Signaling in Cancer Progression

Current Cancer Drug Targets ◽

10.2174/1568009617666170522094730 ◽

2018 ◽

Vol 18 (3) ◽

pp. 256-265 ◽

Cited By ~ 2

Author(s):

Yong Teng ◽

Liwei lang ◽

Catherine E. Jauregui

Keyword(s):

Cancer Progression ◽

Drug Target ◽

Diagnostic Marker ◽

Cell Phenotype ◽

Regulation Of Transcription ◽

Cellular Processes ◽

Human Genes ◽

Cancer Initiation ◽

Chromatin Structural ◽

And Function

The DNA binding protein and chromatin structural regulator DEK regulate many cellular processes. These include proliferation, differentiation, apoptosis, senescence, DNA repairing and the maintenance of stem cell phenotype. DEK is increasingly recognized as a crucial player in many steps of cancer initiation and progression, and is precisely regulated by abundant promoting and inhibiting factors directly or indirectly. DEK may serve as an architectural modulating protein to regulate the expression and function of multiple human genes in cancer cells. In this article we have reviewed the specificities and complexities of DEK in the regulation of transcription factors and global chromatin, including its biologic roles in malignant cells, and summarized the current research. The possible use of DEK as a diagnostic marker and drug target in the prevention or treatment of tumors is also discussed.

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Bend, Push, Stretch: Remarkable Structure and Mechanics of Single Intermediate Filaments and Meshworks

Cells ◽

10.3390/cells10081960 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1960

Author(s):

K. Tanuj Sapra ◽

Ohad Medalia

Keyword(s):

Intermediate Filaments ◽

Eukaryotic Cell ◽

Coiled Coils ◽

Cellular Functions ◽

Mechanical Pressure ◽

Mechanical Feature ◽

Cellular Processes ◽

Nuclear Lamins ◽

Filament Networks ◽

And Function

The cytoskeleton of the eukaryotic cell provides a structural and functional scaffold enabling biochemical and cellular functions. While actin and microtubules form the main framework of the cell, intermediate filament networks provide unique mechanical properties that increase the resilience of both the cytoplasm and the nucleus, thereby maintaining cellular function while under mechanical pressure. Intermediate filaments (IFs) are imperative to a plethora of regulatory and signaling functions in mechanotransduction. Mutations in all types of IF proteins are known to affect the architectural integrity and function of cellular processes, leading to debilitating diseases. The basic building block of all IFs are elongated α-helical coiled-coils that assemble hierarchically into complex meshworks. A remarkable mechanical feature of IFs is the capability of coiled-coils to metamorphize into β-sheets under stress, making them one of the strongest and most resilient mechanical entities in nature. Here, we discuss structural and mechanical aspects of IFs with a focus on nuclear lamins and vimentin.

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The Role of lncRNA in the Development of Tumors, Including Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22168427 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8427

Author(s):

Beata Smolarz ◽

Anna Zadrożna-Nowak ◽

Hanna Romanowicz

Keyword(s):

Breast Cancer ◽

Breast Carcinoma ◽

Present Article ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Regulation Of Transcription ◽

Ribonucleic Acids ◽

Detailed Review ◽

Cellular Processes

Long noncoding RNAs (lncRNAs) are the largest groups of ribonucleic acids, but, despite the increasing amount of literature data, the least understood. Given the involvement of lncRNA in basic cellular processes, especially in the regulation of transcription, the role of these noncoding molecules seems to be of great importance for the proper functioning of the organism. Studies have shown a relationship between disturbed lncRNA expression and the pathogenesis of many diseases, including cancer. The present article presents a detailed review of the latest reports and data regarding the importance of lncRNA in the development of cancers, including breast carcinoma.

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Targeting the Cerebrovascular System: Next-Generation Biomarkers and Treatment for Mild Traumatic Brain Injury

The Neuroscientist ◽

10.1177/10738584211012264 ◽

2021 ◽

pp. 107385842110122

Author(s):

Tamara L. Baker ◽

Denes V. Agoston ◽

Rhys D. Brady ◽

Brendan Major ◽

Stuart J. McDonald ◽

...

Keyword(s):

Brain Function ◽

Brain Injuries ◽

Neurological Dysfunction ◽

Clinical Approach ◽

Cerebral Vasculature ◽

Review Of The Literature ◽

Cerebrovascular Injury ◽

Medical Issues ◽

And Function ◽

Cerebrovascular System

The diagnosis, prognosis, and treatment of mild traumatic brain injuries (mTBIs), such as concussions, are significant unmet medical issues. The kinetic forces that occur in mTBI adversely affect the cerebral vasculature, making cerebrovascular injury (CVI) a pathophysiological hallmark of mTBI. Given the importance of a healthy cerebrovascular system in overall brain function, CVI is likely to contribute to neurological dysfunction after mTBI. As such, CVI and related pathomechanisms may provide objective biomarkers and therapeutic targets to improve the clinical management and outcomes of mTBI. Despite this potential, until recently, few studies have focused on the cerebral vasculature in this context. This article will begin by providing a brief overview of the cerebrovascular system followed by a review of the literature regarding how mTBI can affect the integrity and function of the cerebrovascular system, and how this may ultimately contribute to neurological dysfunction and neurodegenerative conditions. We then discuss promising avenues of research related to mTBI biomarkers and interventions that target CVI, and conclude that a clinical approach that takes CVI into account could result in substantial improvements in the care and outcomes of patients with mTBI.

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The long noncoding RNA Synage regulates synapse stability and neuronal function in the cerebellum

Cell Death and Differentiation ◽

10.1038/s41418-021-00774-3 ◽

2021 ◽

Author(s):

Fei Wang ◽

Qianqian Wang ◽

Baowei Liu ◽

Lisheng Mei ◽

Sisi Ma ◽

...

Keyword(s):

Noncoding Rna ◽

Cerebellar Atrophy ◽

Synaptic Activity ◽

Motor Dysfunction ◽

Cerebellar Development ◽

Full Spectrum ◽

Density Reduction ◽

Adult Mice ◽

Synapse Density ◽

And Function

AbstractThe brain is known to express many long noncoding RNAs (lncRNAs); however, whether and how these lncRNAs function in modulating synaptic stability remains unclear. Here, we report a cerebellum highly expressed lncRNA, Synage, regulating synaptic stability via at least two mechanisms. One is through the function of Synage as a sponge for the microRNA miR-325-3p, to regulate expression of the known cerebellar synapse organizer Cbln1. The other function is to serve as a scaffold for organizing the assembly of the LRP1-HSP90AA1-PSD-95 complex in PF-PC synapses. Although somewhat divergent in its mature mRNA sequence, the locus encoding Synage is positioned adjacent to the Cbln1 loci in mouse, rhesus macaque, and human, and Synage is highly expressed in the cerebella of all three species. Synage deletion causes a full-spectrum cerebellar ablation phenotype that proceeds from cerebellar atrophy, through neuron loss, on to synapse density reduction, synaptic vesicle loss, and finally to a reduction in synaptic activity during cerebellar development; these deficits are accompanied by motor dysfunction in adult mice, which can be rescued by AAV-mediated Synage overexpression from birth. Thus, our study demonstrates roles for the lncRNA Synage in regulating synaptic stability and function during cerebellar development.

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Ubiquitin and Ubiquitin-Like Proteins and Domains in Ribosome Production and Function: Chance or Necessity?

International Journal of Molecular Sciences ◽

10.3390/ijms22094359 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4359

Author(s):

Sara Martín-Villanueva ◽

Gabriel Gutiérrez ◽

Dieter Kressler ◽

Jesús de la Cruz

Keyword(s):

Ribosomal Proteins ◽

Ribosome Biogenesis ◽

Ribosome Assembly ◽

Cellular Processes ◽

Substrate Protein ◽

Precursor Proteins ◽

Assembly Factors ◽

Ubiquitin Moiety ◽

And Function

Ubiquitin is a small protein that is highly conserved throughout eukaryotes. It operates as a reversible post-translational modifier through a process known as ubiquitination, which involves the addition of one or several ubiquitin moieties to a substrate protein. These modifications mark proteins for proteasome-dependent degradation or alter their localization or activity in a variety of cellular processes. In most eukaryotes, ubiquitin is generated by the proteolytic cleavage of precursor proteins in which it is fused either to itself, constituting a polyubiquitin precursor, or as a single N-terminal moiety to ribosomal proteins, which are practically invariably eL40 and eS31. Herein, we summarize the contribution of the ubiquitin moiety within precursors of ribosomal proteins to ribosome biogenesis and function and discuss the biological relevance of having maintained the explicit fusion to eL40 and eS31 during evolution. There are other ubiquitin-like proteins, which also work as post-translational modifiers, among them the small ubiquitin-like modifier (SUMO). Both ubiquitin and SUMO are able to modify ribosome assembly factors and ribosomal proteins to regulate ribosome biogenesis and function. Strikingly, ubiquitin-like domains are also found within two ribosome assembly factors; hence, the functional role of these proteins will also be highlighted.

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Akt2 Regulates Cardiac Metabolism and Cardiomyocyte Survival

Journal of Biological Chemistry ◽

10.1074/jbc.m513087200 ◽

2006 ◽

Vol 281 (43) ◽

pp. 32841-32851 ◽

Cited By ~ 110

Author(s):

Brian DeBosch ◽

Nandakumar Sambandam ◽

Carla Weinheimer ◽

Michael Courtois ◽

Anthony J. Muslin

Keyword(s):

Pressure Overload ◽

Cardiac Metabolism ◽

Cellular Protein ◽

Growth Responses ◽

Infarct Zone ◽

Targeted Disruption ◽

Cellular Processes ◽

Ligand Stimulation ◽

And Function

The Akt family of serine-threonine kinases participates in diverse cellular processes, including the promotion of cell survival, glucose metabolism, and cellular protein synthesis. All three known Akt family members, Akt1, Akt2 and Akt3, are expressed in the myocardium, although Akt1 and Akt2 are most abundant. Previous studies demonstrated that Akt1 and Akt3 overexpression results in enhanced myocardial size and function. Yet, little is known about the role of Akt2 in modulating cardiac metabolism, survival, and growth. Here, we utilize murine models with targeted disruption of the akt2 or the akt1 genes to demonstrate that Akt2, but not Akt1, is required for insulin-stimulated 2-[3H]deoxyglucose uptake and metabolism. In contrast, akt2-/- mice displayed normal cardiac growth responses to provocative stimulation, including ligand stimulation of cultured cardiomyocytes, pressure overload by transverse aortic constriction, and myocardial infarction. However, akt2-/- mice were found to be sensitized to cardiomyocyte apoptosis in response to ischemic injury, and apoptosis was significantly increased in the peri-infarct zone of akt2-/- hearts 7 days after occlusion of the left coronary artery. These results implicate Akt2 in the regulation of cardiomyocyte metabolism and survival.

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Bioerodible Polypyrrole

MRS Proceedings ◽

10.1557/proc-711-gg2.7.1 ◽

2001 ◽

Vol 711 ◽

Cited By ~ 1

Author(s):

Alexander Zelikin ◽

Venkatram Shastri ◽

David Lynn ◽

Jian Farhadi ◽

Ivan Martin ◽

...

Keyword(s):

Erosion Rate ◽

Acid Group ◽

The Novel ◽

Carboxylic Acid Group ◽

Polymer Backbone ◽

Cellular Processes ◽

Novel Approach ◽

Efficient Control ◽

And Function ◽

Substrate Independent

ABSTRACTConductive polymers such as polypyrrole (Ppy) are potentially useful as an active interface for altering cellular processes and function. Their utilization in medically related applications however have been substantially held back by their non-degradable nature. Herein we report a novel approach to creation of bioerodible polypyrroles via modification of pyrrole beta-carbon with an ionizable moiety. It has been shown that the erosion rate of acid-bearing derivative of polypyrrole increases with pH, which is consistent with the pH dependent ionization of carboxylic acid group. The novel paradigm proposed for the creation of bioerodible polypyrroles allows for simple and efficient control over the erosion rate of the substrate independent of the polymer chain length, via the choice of the terminal ionizable group and its concentration along the polymer backbone.

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A Potential of microRNAs for High-Content Screening

Journal of Nucleic Acids ◽

10.4061/2011/870903 ◽

2011 ◽

Vol 2011 ◽

pp. 1-15 ◽

Cited By ~ 9

Author(s):

Andrius Serva ◽

Christoph Claas ◽

Vytaute Starkuviene

Keyword(s):

Large Scale ◽

Cellular Processes ◽

Comprehensive Knowledge ◽

Functional Models ◽

Rapid Accumulation ◽

Health And Disease ◽

Temporal And Spatial ◽

And Function ◽

Functional Analyses ◽

Immense Potential

In the last years miRNAs have increasingly been recognised as potent posttranscriptional regulators of gene expression. Possibly, miRNAs exert their action on virtually any biological process by simultaneous regulation of numerous genes. The importance of miRNA-based regulation in health and disease has inspired research to investigate diverse aspects of miRNA origin, biogenesis, and function. Despite the recent rapid accumulation of experimental data, and the emergence of functional models, the complexity of miRNA-based regulation is still far from being well understood. In particular, we lack comprehensive knowledge as to which cellular processes are regulated by which miRNAs, and, furthermore, how temporal and spatial interactions of miRNAs to their targets occur. Results from large-scale functional analyses have immense potential to address these questions. In this review, we discuss the latest progress in application of high-content and high-throughput functional analysis for the systematic elucidation of the biological roles of miRNAs.

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Chromatin regulates expression of small RNAs to help maintain transposon methylome homeostasis in Arabidopsis

Genome Biology ◽

10.1186/s13059-020-02163-4 ◽

2020 ◽

Vol 21 (1) ◽

Cited By ~ 3

Author(s):

Ranjith K. Papareddy ◽

Katalin Páldi ◽

Subramanian Paulraj ◽

Ping Kao ◽

Stefan Lutzmayer ◽

...

Keyword(s):

Growth And Development ◽

Germ Line ◽

Small Interfering Rnas ◽

Chromatin States ◽

Heterochromatin Formation ◽

Cellular Processes ◽

A Cell ◽

Decondensed Chromatin ◽

And Function ◽

New Generation

Abstract Background Eukaryotic genomes are partitioned into euchromatic and heterochromatic domains to regulate gene expression and other fundamental cellular processes. However, chromatin is dynamic during growth and development and must be properly re-established after its decondensation. Small interfering RNAs (siRNAs) promote heterochromatin formation, but little is known about how chromatin regulates siRNA expression. Results We demonstrate that thousands of transposable elements (TEs) produce exceptionally high levels of siRNAs in Arabidopsis thaliana embryos. TEs generate siRNAs throughout embryogenesis according to two distinct patterns depending on whether they are located in euchromatic or heterochromatic regions of the genome. siRNA precursors are transcribed in embryos, and siRNAs are required to direct the re-establishment of DNA methylation on TEs from which they are derived in the new generation. Decondensed chromatin also permits the production of 24-nt siRNAs from heterochromatic TEs during post-embryogenesis, and siRNA production from bipartite-classified TEs is controlled by their chromatin states. Conclusions Decondensation of heterochromatin in response to developmental, and perhaps environmental, cues promotes the transcription and function of siRNAs in plants. Our results indicate that chromatin-mediated siRNA transcription provides a cell-autonomous homeostatic control mechanism to help reconstitute pre-existing chromatin states during growth and development including those that ensure silencing of TEs in the future germ line.

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