Regulation of signalling by microRNAs

Stringent regulation of biochemical signalling pathways involves feedback and feedforward loops, which underlie robust cellular responses to external stimuli. Regulation occurs in all horizontal layers of signalling networks, primarily by proteins that mediate internalization of receptor–ligand complexes, dephosphorylation of kinases and their substrates, as well as transcriptional repression. Recent studies have unveiled the role of miRNAs (microRNAs), post-transcriptional regulators that control mRNA stability, as key modulators of signal propagation. By acting as genetic switches or fine-tuners, miRNAs can directly and multiply regulate cellular outcomes in response to diverse extracellular signals. Conversely, signalling networks temporally control stability, biogenesis and abundance of miRNAs, by regulating layers of the miRNA biogenesis pathway. In the present mini-review, we use a set of examples to illustrate the extensive interdependence between miRNAs and signalling networks.

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Nuclear ErbB2 represses DEPTOR transcription to inhibit autophagy in breast cancer cells

Cell Death and Disease ◽

10.1038/s41419-021-03686-9 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Yanli Bi ◽

Longyuan Gong ◽

Pengyuan Liu ◽

Xiufang Xiong ◽

Yongchao Zhao

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Transcriptional Repression ◽

Breast Cancer Cells ◽

Kinase Activity ◽

Nuclear Translocation ◽

Extracellular Signals ◽

Consensus Binding Sequence ◽

Binding Sequence

AbstractErbB2, a classical receptor tyrosine kinase, is frequently overexpressed in breast cancer cells. Although the role of ErbB2 in the transmission of extracellular signals to intracellular matrix has been widely studied, the functions of nuclear ErbB2 remain largely elusive. Here, we report a novel function of nuclear ErbB2 in repressing the transcription of DEPTOR, a direct inhibitor of mTOR. Nuclear ErbB2 directly binds to the consensus binding sequence in the DEPTOR promoter to repress its transcription. The kinase activity of ErbB2 is required for its nuclear translocation and transcriptional repression of DEPTOR. Moreover, the repressed DEPTOR by nuclear ErbB2 inhibits the induction of autophagy by activating mTORC1. Thus, our study reveals a novel mechanism for autophagy regulation by functional ErbB2, which translocates to the nucleus and acts as a transcriptional regulator to suppress DEPTOR transcription, leading to activation of the PI3K/AKT/mTOR pathway to inhibit autophagy.

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The Role of MAPK in Drug-Induced Kidney Injury

Journal of Signal Transduction ◽

10.1155/2012/463617 ◽

2012 ◽

Vol 2012 ◽

pp. 1-15 ◽

Cited By ~ 20

Author(s):

Hilary Cassidy ◽

Robert Radford ◽

Jennifer Slyne ◽

Sein O’Connell ◽

Craig Slattery ◽

...

Keyword(s):

Kidney Injury ◽

Cellular Responses ◽

Drug Induced ◽

Mapk Signalling ◽

Transmission Of Information ◽

Different Types ◽

Mitogen Activated Protein ◽

External Stimuli ◽

Effective Transmission

This paper focuses on the role that mitogen-activated protein kinases (MAPKs) play in drug-induced kidney injury. The MAPKs, of which there are four major classes (ERK, p38, JNK, and ERK5/BMK), are signalling cascades which have been found to be broadly conserved across a wide variety of organisms. MAPKs allow effective transmission of information from the cell surface to the cytosolic or nuclear compartments. Cross talk between the MAPKs themselves and with other signalling pathways allows the cell to modulate responses to a wide variety of external stimuli. The MAPKs have been shown to play key roles in both mediating and ameliorating cellular responses to stress including xenobiotic-induced toxicity. Therefore, this paper will discuss the specific role of the MAPKs in the kidney in response to injury by a variety of xenobiotics and the potential for therapeutic intervention at the level of MAPK signalling across different types of kidney disease.

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ERH facilitates microRNA maturation through the interaction with the N-terminus of DGCR8

Nucleic Acids Research ◽

10.1093/nar/gkaa827 ◽

2020 ◽

Vol 48 (19) ◽

pp. 11097-11112

Author(s):

S Chul Kwon ◽

Harim Jang ◽

Siyuan Shen ◽

S Chan Baek ◽

Kijun Kim ◽

...

Keyword(s):

Mirna Biogenesis ◽

Rnase Iii ◽

Primary Transcript ◽

High Affinity ◽

Hydrophobic Groove ◽

Dsrna Binding ◽

N Terminus ◽

Mirna Clusters ◽

Mirna Biogenesis Pathway

Abstract The microprocessor complex cleaves the primary transcript of microRNA (pri-miRNA) to initiate miRNA maturation. Microprocessor is known to consist of RNase III DROSHA and dsRNA-binding DGCR8. Here, we identify Enhancer of Rudimentary Homolog (ERH) as a new component of Microprocessor. Through a crystal structure and biochemical experiments, we reveal that ERH uses its hydrophobic groove to bind to a conserved region in the N-terminus of DGCR8, in a 2:2 stoichiometry. Knock-down of ERH or deletion of the DGCR8 N-terminus results in a reduced processing of suboptimal pri-miRNAs in polycistronic miRNA clusters. ERH increases the processing of suboptimal pri-miR-451 in a manner dependent on its neighboring pri-miR-144. Thus, the ERH dimer may mediate ‘cluster assistance’ in which Microprocessor is loaded onto a poor substrate with help from a high-affinity substrate in the same cluster. Our study reveals a role of ERH in the miRNA biogenesis pathway.

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Leading Professionals

10.1093/oso/9780198744788.001.0001 ◽

2017 ◽

Cited By ~ 6

Author(s):

Laura Empson

Keyword(s):

Mergers And Acquisitions ◽

Distributed Leadership ◽

Investment Banks ◽

Professional Organizations ◽

Power Dynamics ◽

Consulting Firms ◽

Complex Power ◽

Plural Leadership ◽

External Stimuli

This book analyses the complex power dynamics and interpersonal politics that lie at the heart of leadership in professional organizations, such as accounting, law, and consulting firms, investment banks, hospitals, and universities. It is based on scholarly research into many of the world’s leading professional organizations across a range of sectors, including interviews with over 500 senior professionals in sixteen countries. Drawing on the latest academic theory to analyse exactly how professionals in organizations come together to create ‘leadership’, it provides new insights into how leaders lead when there is no traditional hierarchy to support them, their own authority is contingent, and they must constantly renegotiate relationships with relatively autonomous professional peers. It explores how leaders persuade highly intelligent, educated, and opinionated professionals to work together; how change happens within professional organizations; and why leaders so often fail. Part I introduces the concept of plural leadership, analysing how leaders establish and maintain their positions within leadership constellations, and the implications for governance in the context of collective or distributed leadership. Part II examines the complex, challenging relationships between professionals as they seek to influence their organizations, including the phenomena of leadership dyads, insecure overachievers, social control, and the rise of the management professional. Part III examines the shifts in the locus of power as professional organizations grow, adapt, and react to external stimuli such as mergers and acquisitions and economic crises. The conclusion identifies the paradoxes inherent in professional organizations and examines the role of leaders in attempting to reconcile them.

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Phosphorylation of GAPVD1 Is Regulated by the PER Complex and Linked to GAPVD1 Degradation

International Journal of Molecular Sciences ◽

10.3390/ijms22073787 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3787

Author(s):

Hussam Ibrahim ◽

Philipp Reus ◽

Anna Katharina Mundorf ◽

Anna-Lena Grothoff ◽

Valerie Rudenko ◽

...

Keyword(s):

Circadian Clock ◽

Transcriptional Repression ◽

Small Gtpase ◽

Main Role ◽

Interacting Proteins ◽

Casein Kinase 1 ◽

Bona Fide ◽

Kinetics Of

Repressor protein period (PER) complexes play a central role in the molecular oscillator mechanism of the mammalian circadian clock. While the main role of nuclear PER complexes is transcriptional repression, much less is known about the functions of cytoplasmic PER complexes. We found with a biochemical screen for PER2-interacting proteins that the small GTPase regulator GTPase-activating protein and VPS9 domain-containing protein 1 (GAPVD1), which has been identified previously as a component of cytoplasmic PER complexes in mice, is also a bona fide component of human PER complexes. We show that in situ GAPVD1 is closely associated with casein kinase 1 delta (CSNK1D), a kinase that regulates PER2 levels through a phosphoswitch mechanism, and that CSNK1D regulates the phosphorylation of GAPVD1. Moreover, phosphorylation determines the kinetics of GAPVD1 degradation and is controlled by PER2 and a C-terminal autoinhibitory domain in CSNK1D, indicating that the regulation of GAPVD1 phosphorylation is a novel function of cytoplasmic PER complexes and might be part of the oscillator mechanism or an output function of the circadian clock.

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Genetic Analysis of the Role of Pol II Holoenzyme Components in Repression by the Cyc8-Tup1 Corepressor in Yeast

Genetics ◽

10.1093/genetics/155.4.1535 ◽

2000 ◽

Vol 155 (4) ◽

pp. 1535-1542 ◽

Cited By ~ 3

Author(s):

Mark Lee ◽

Sukalyan Chatterjee ◽

Kevin Struhl

Keyword(s):

Transcriptional Repression ◽

Detectable Effect ◽

Genetic Screens ◽

Phenotypic Analysis ◽

Histone Tails ◽

Pol Ii ◽

Corepressor Complex ◽

The Individual ◽

Modest Effect

Abstract The Cyc8-Tup1 corepressor complex is targeted to promoters by pathway-specific DNA-binding repressors, thereby inhibiting the transcription of specific classes of genes. Genetic screens have identified mutations in a variety of Pol II holoenzyme components (Srb8, Srb9, Srb10, Srb11, Sin4, Rgr1, Rox3, and Hrs1) and in the N-terminal tails of histones H3 and H4 that weaken repression by Cyc8-Tup1. Here, we analyze the effect of individual and multiple mutations in many of these components on transcriptional repression of natural promoters that are regulated by Cyc8-Tup1. In all cases tested, individual mutations have a very modest effect on SUC2 RNA levels and no detectable effect on levels of ANB1, MFA2, and RNR2. Furthermore, multiple mutations within the Srb components, between Srbs and Sin4, and between Srbs and histone tails affect Cyc8-Tup1 repression to the same modest extent as the individual mutations. These results argue that the weak effects of the various mutations on repression by Cyc8-Tup1 are not due to redundancy among components of the Pol II machinery, and they argue against a simple redundancy between the holoenzyme and chromatin pathways. In addition, phenotypic analysis indicates that, although Srbs8–11 are indistinguishable with respect to Cyc8-Tup1 repression, the individual Srbs are functionally distinct in other respects. Genetic interactions among srb mutations imply that a balance between the activities of Srb8 + Srb10 and Srb11 is important for normal cell growth.

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Emerging multifaceted roles of BAP1 complexes in biological processes

Cell Death Discovery ◽

10.1038/s41420-021-00406-2 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Aileen Patricia Szczepanski ◽

Lu Wang

Keyword(s):

Transcriptional Repression ◽

Target Genes ◽

Regulatory Mechanisms ◽

Biological Processes ◽

Multiprotein Complex ◽

Downstream Target ◽

Evolutionarily Conserved ◽

Complex Forms ◽

Polycomb Repressive Complex 1

AbstractHistone H2AK119 mono-ubiquitination (H2AK119Ub) is a relatively abundant histone modification, mainly catalyzed by the Polycomb Repressive Complex 1 (PRC1) to regulate Polycomb-mediated transcriptional repression of downstream target genes. Consequently, H2AK119Ub can also be dynamically reversed by the BAP1 complex, an evolutionarily conserved multiprotein complex that functions as a general transcriptional activator. In previous studies, it has been reported that the BAP1 complex consists of important biological roles in development, metabolism, and cancer. However, identifying the BAP1 complex’s regulatory mechanisms remains to be elucidated due to its various complex forms and its ability to target non-histone substrates. In this review, we will summarize recent findings that have contributed to the diverse functional role of the BAP1 complex and further discuss the potential in targeting BAP1 for therapeutic use.

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T cell–specific STAT3 deficiency abrogates lupus nephritis

Lupus ◽

10.1177/0961203319877242 ◽

2019 ◽

Vol 28 (12) ◽

pp. 1468-1472 ◽

Cited By ~ 2

Author(s):

N Yoshida ◽

F He ◽

V C Kyttaris

Keyword(s):

T Cells ◽

T Cell ◽

Lupus Nephritis ◽

Lupus Erythematosus ◽

Cell Responses ◽

Cytokines And Chemokines ◽

Novel Approach ◽

Cell Tissue ◽

External Stimuli

Signal transducer and activator of transcription (STAT) 3 is a regulator of T-cell responses to external stimuli, such as pro-inflammatory cytokines and chemokines. We have previously shown that STAT3 is activated (phosphorylated) at high levels in systemic lupus erythematosus (SLE) T cells and mediates chemokine-induced migration and T:B cell interactions. Stattic, a small molecular STAT3 inhibitor, can partially ameliorate lupus nephritis in mice. To understand the role of STAT3 better in T-cell pathophysiology in lupus nephritis and its potential as a treatment target, we silenced its expression in T cells using a cd4-driven CRE-Flox model. We found that lupus-prone mice that do not express STAT3 in T cells did not develop lymphadenopathy, splenomegaly, or glomerulonephritis. Moreover, the production of anti-dsDNA antibodies was decreased in these mice compared to controls. To dissect the mechanism, we also used a nephrotoxic serum model of nephritis. In this model, T cell–specific silencing of STAT3 resulted in amelioration of nephrotoxic serum-induced kidney damage. Taken together, our results suggest that in mouse models of autoimmune nephritis, T cell–specific silencing of STAT3 can hamper their ability to help B cells to produce autoantibodies and induce cell tissue infiltration. We propose that STAT3 inhibition in T cells represents a novel approach in the treatment of SLE and lupus nephritis in particular.

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SOS2 Comes to the Fore: Differential Functionalities in Physiology and Pathology

International Journal of Molecular Sciences ◽

10.3390/ijms22126613 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6613

Author(s):

Fernando C. Baltanás ◽

Rósula García-Navas ◽

Eugenio Santos

Keyword(s):

Expression Patterns ◽

Critical Role ◽

Ras Signaling ◽

Epidermal Stem Cell ◽

Functional Specificity ◽

Functional Roles ◽

Signaling Axis ◽

Therapy Target ◽

External Stimuli

The SOS family of Ras-GEFs encompasses two highly homologous and widely expressed members, SOS1 and SOS2. Despite their similar structures and expression patterns, early studies of constitutive KO mice showing that SOS1-KO mutants were embryonic lethal while SOS2-KO mice were viable led to initially viewing SOS1 as the main Ras-GEF linking external stimuli to downstream RAS signaling, while obviating the functional significance of SOS2. Subsequently, different genetic and/or pharmacological ablation tools defined more precisely the functional specificity/redundancy of the SOS1/2 GEFs. Interestingly, the defective phenotypes observed in concomitantly ablated SOS1/2-DKO contexts are frequently much stronger than in single SOS1-KO scenarios and undetectable in single SOS2-KO cells, demonstrating functional redundancy between them and suggesting an ancillary role of SOS2 in the absence of SOS1. Preferential SOS1 role was also demonstrated in different RASopathies and tumors. Conversely, specific SOS2 functions, including a critical role in regulation of the RAS–PI3K/AKT signaling axis in keratinocytes and KRAS-driven tumor lines or in control of epidermal stem cell homeostasis, were also reported. Specific SOS2 mutations were also identified in some RASopathies and cancer forms. The relevance/specificity of the newly uncovered functional roles suggests that SOS2 should join SOS1 for consideration as a relevant biomarker/therapy target.

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