Role of Sp1 in insulin regulation of gene expression

Sp1 is a ubiquitous nuclear factor that plays a key role in maintaining basal transcription of 'house-keeping' genes. However, recent evidence points to a more important function for Sp1 in mediating 'cross-talk' between selected signaling cascades to regulate the target genes that respond to these pathways. The role of Sp1 in mediating the actions of the peptide hormone insulin is of specific interest and serves as a model for detailing effects of intracellular signaling on Sp1 activity. This review summarizes studies suggesting that changes in Sp1 phosphorylation provide one potential mechanism for manipulating activity of this protein. A growing body of evidence reveals that the DNA binding and transcription activity of Sp1 may increase or decrease in response to changes in phosphorylation. This enables 'fine-tuning' of Sp1 activity for regulation of gene transcription. Several mechanisms exist by which Sp1 alters gene activity in response to insulin. These include independent Sp1 activity as well as collaboration or competition with others factors. This review points to an ever-increasing role for Sp1 in regulating the transcription of genes in response to extracellular signals such as insulin.

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The Pleiotropic Intricacies of Hedgehog Signaling: From Craniofacial Patterning to Carcinogenesis

FACE ◽

10.1177/27325016211024326 ◽

2021 ◽

pp. 273250162110243

Author(s):

Mikhail Pakvasa ◽

Andrew B. Tucker ◽

Timothy Shen ◽

Tong-Chuan He ◽

Russell R. Reid

Keyword(s):

Intracellular Signaling ◽

Limb Development ◽

Hedgehog Signaling ◽

Target Genes ◽

Craniofacial Development ◽

Signaling Cascade ◽

Signaling Mechanisms ◽

Intracellular Signaling Cascade ◽

And Function

Hedgehog signaling was discovered more than 40 years ago in experiments demonstrating that it is a fundamental mediator of limb development. Since that time, it has been shown to be important in development, homeostasis, and disease. The hedgehog pathway proceeds through a pathway highly conserved throughout animals beginning with the extracellular diffusion of hedgehog ligands, proceeding through an intracellular signaling cascade, and ending with the activation of specific target genes. A vast amount of research has been done elucidating hedgehog signaling mechanisms and regulation. This research has found a complex system of genetics and signaling that helps determine how organisms develop and function. This review provides an overview of what is known about hedgehog genetics and signaling, followed by an in-depth discussion of the role of hedgehog signaling in craniofacial development and carcinogenesis.

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Microglia in cerebral ischemia: molecular actions and interactionsThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigator's Forum.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y05-143 ◽

2006 ◽

Vol 84 (1) ◽

pp. 49-59 ◽

Cited By ~ 121

Author(s):

Aaron Y. Lai ◽

Kathryn G. Todd

Keyword(s):

Cerebral Ischemia ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Extracellular Signals ◽

Messenger Molecules ◽

Membrane Bound ◽

The Subject ◽

Survey Review ◽

Selection Of

The precise role of microglia in stroke and cerebral ischemia has been the subject of debate for a number of years. Microglia are capable of synthesizing numerous soluble and membrane-bound biomolecules, some known to be neuroprotective, some neurotoxic, whereas others have less definitive bioactivities. The molecular mechanisms through which microglia activate these molecules have thus become an important area of ischemia research. Here we provide a survey review that summarizes the key actions of microglial factors in cerebral ischemia including complement proteins, chemokines, pro-inflammatory cytokines, neurotrophic factors, hormones, and proteinases, as well several important messenger molecules that play a part in how these factors respond to extracellular signals during ischemic injuries. We also provide some new perspectives on how microglial intracellular signaling may contribute to the seemingly contradictory roles of several microglial effector molecules.

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Phosphorylation Sites in Protein Kinases and Phosphatases Regulated by Formyl Peptide Receptor 2 Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms21113818 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3818

Author(s):

Maria Carmela Annunziata ◽

Melania Parisi ◽

Gabriella Esposito ◽

Gabriella Fabbrocini ◽

Rosario Ammendola ◽

...

Keyword(s):

Protein Kinase ◽

Protein Kinases ◽

Protein Phosphatase ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Fine Tuning ◽

Formyl Peptide Receptor ◽

Signaling Cascades ◽

Regulatory Subunit ◽

Formyl Peptides

FPR1, FPR2, and FPR3 are members of Formyl Peptides Receptors (FPRs) family belonging to the GPCR superfamily. FPR2 is a low affinity receptor for formyl peptides and it is considered the most promiscuous member of this family. Intracellular signaling cascades triggered by FPRs include the activation of different protein kinases and phosphatase, as well as tyrosine kinase receptors transactivation. Protein kinases and phosphatases act coordinately and any impairment of their activation or regulation represents one of the most common causes of several human diseases. Several phospho-sites has been identified in protein kinases and phosphatases, whose role may be to expand the repertoire of molecular mechanisms of regulation or may be necessary for fine-tuning of switch properties. We previously performed a phospho-proteomic analysis in FPR2-stimulated cells that revealed, among other things, not yet identified phospho-sites on six protein kinases and one protein phosphatase. Herein, we discuss on the selective phosphorylation of Serine/Threonine-protein kinase N2, Serine/Threonine-protein kinase PRP4 homolog, Serine/Threonine-protein kinase MARK2, Serine/Threonine-protein kinase PAK4, Serine/Threonine-protein kinase 10, Dual specificity mitogen-activated protein kinase kinase 2, and Protein phosphatase 1 regulatory subunit 14A, triggered by FPR2 stimulation. We also describe the putative FPR2-dependent signaling cascades upstream to these specific phospho-sites.

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Phospho-Mimetic Mutation at Ser602 Inactivates Human TRPA1 Channel

International Journal of Molecular Sciences ◽

10.3390/ijms21217995 ◽

2020 ◽

Vol 21 (21) ◽

pp. 7995

Author(s):

Kristyna Barvikova ◽

Ivan Barvik ◽

Viktor Sinica ◽

Lucie Zimova ◽

Viktorie Vlachova

Keyword(s):

Intracellular Signaling ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Conformational Space ◽

Signaling Cascades ◽

Post Translational Modifications ◽

Allosteric Coupling ◽

Structural Impact ◽

Transient Receptor

The Transient Receptor Potential Ankyrin 1 (TRPA1) channel is an integrative molecular sensor for detecting environmental irritant compounds, endogenous proalgesic and inflammatory agents, pressure, and temperature. Different post-translational modifications participate in the discrimination of the essential functions of TRPA1 in its physiological environment, but the underlying structural bases are poorly understood. Here, we explored the role of the cytosolic N-terminal residue Ser602 located near a functionally important allosteric coupling domain as a potential target of phosphorylation. The phosphomimetic mutation S602D completely abrogated channel activation, whereas the phosphonull mutations S602G and S602N produced a fully functional channel. Using mutagenesis, electrophysiology, and molecular simulations, we investigated the possible structural impact of a modification (mutation or phosphorylation) of Ser602 and found that this residue represents an important regulatory site through which the intracellular signaling cascades may act to reversibly restrict or “dampen” the conformational space of the TRPA1 channel and promote its transitions to the closed state.

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Ewing Sarcoma Protein: A Key Player in Human Cancer

International Journal of Cell Biology ◽

10.1155/2013/642853 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 39

Author(s):

Maria Paola Paronetto

Keyword(s):

Ewing Sarcoma ◽

Cancer Biology ◽

Genome Stability ◽

Rna Binding ◽

Human Cancer ◽

Neuromuscular Disorders ◽

Regulation Of Gene Expression ◽

Protein A ◽

Structural Features

The Ewing sarcoma protein (EWS) is a well-known player in cancer biology for the specific translocations occurring in sarcomas. The EWS-FLI1 gene fusion is the prototypical translocation that encodes the aberrant, chimeric transcription factor, which is a landmark of Ewing tumors. In all described Ewing sarcoma oncogenes, the EWS RNA binding domains are completely missing; thus RNA binding properties are not retained in the hybrid proteins. However, it is currently unknown whether the absence of EWS function in RNA metabolism plays a role in oncogenic transformation or if EWS plays a role by itself in cancer development besides its contribution to the translocation. In this regard, recent reports have highlighted an essential role for EWS in the regulation of DNA damage response (DDR), a process that counteracts genome stability and is often deregulated in cancer cells. The first part of this review will describe the structural features of EWS and its multiple roles in the regulation of gene expression, which are exerted by coordinating different steps in the synthesis and processing of pre-mRNAs. The second part will examine the role of EWS in the regulation of DDR- and cancer-related genes, with potential implications in cancer therapies. Finally, recent advances on the involvement of EWS in neuromuscular disorders will be discussed. Collectively, the information reviewed herein highlights the broad role of EWS in bridging different cellular processes and underlines the contribution of EWS to genome stability and proper cell-cycle progression in higher eukaryotic cells.

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LncRNA HOTAIR in Tumor Microenvironment: What Role?

International Journal of Molecular Sciences ◽

10.3390/ijms20092279 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2279 ◽

Cited By ~ 15

Author(s):

Gerardo Botti ◽

Giosuè Scognamiglio ◽

Gabriella Aquino ◽

Giuseppina Liguori ◽

Monica Cantile

Keyword(s):

Gene Expression ◽

Tumor Microenvironment ◽

Intracellular Signaling ◽

Regulation Of Gene Expression ◽

Tumor Evolution ◽

Metastatic Progression ◽

Cellular Processes ◽

Cellular Components ◽

Lncrna Hotair

lncRNAs participate in many cellular processes, including regulation of gene expression at the transcriptional and post-transcriptional levels. In addition, many lncRNAs can contribute to the development of different human diseases including cancer. The tumor microenvironment (TME) plays an important role during tumor growth and metastatic progression, and most of these lncRNAs have a key function in TME intracellular signaling. Among the numerous identified lncRNAs, several experimental evidences have shown the fundamental role of the lncRNA HOTAIR in carcinogenesis, also highlighting its use as a circulating biomarker. In this review we described the contribution of HOTAIR in the TME modulation, highlighting its relation with cellular and non-cellular components during tumor evolution and progression.

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Impact of estrogens and estrogen receptor-α in brain lipid metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00473.2017 ◽

2018 ◽

Vol 315 (1) ◽

pp. E7-E14 ◽

Cited By ~ 13

Author(s):

Eugenia Morselli ◽

Roberta de Souza Santos ◽

Su Gao ◽

Yenniffer Ávalos ◽

Alfredo Criollo ◽

...

Keyword(s):

Lipid Metabolism ◽

Intracellular Signaling ◽

Fatty Acid Content ◽

Estrogen Receptor Α ◽

Signaling Cascades ◽

Brain Lipid ◽

Adipose Tissues ◽

The Central Nervous System ◽

The Brain

Estrogens and their receptors play key roles in regulating body weight, energy expenditure, and metabolic homeostasis. It is known that lack of estrogens promotes increased food intake and induces the expansion of adipose tissues, for which much is known. An area of estrogenic research that has received less attention is the role of estrogens and their receptors in influencing intermediary lipid metabolism in organs such as the brain. In this review, we highlight the actions of estrogens and their receptors in regulating their impact on modulating fatty acid content, utilization, and oxidation through their direct impact on intracellular signaling cascades within the central nervous system.

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Hsa-circ-0064636 regulation of the target gene VDAC1/UBE4A by hsa-miR-326/hsa-miR-503-5 in osteosarcoma

10.21203/rs.3.rs-305653/v1 ◽

2021 ◽

Author(s):

Guohua Yan ◽

Hanji Huang ◽

Kanglu Li ◽

Mingjun Zheng ◽

Jiagang Qin ◽

...

Keyword(s):

Cancer Progression ◽

Target Gene ◽

Target Genes ◽

Gene Prediction ◽

Critical Role ◽

Regulation Of Gene Expression ◽

Circular Rnas ◽

Qrt Pcr ◽

Eukaryotic Organisms

Abstract Background: Circular RNAs (circRNAs) are a subclass of noncoding RNAs that play a critical role in the regulation of gene expression in eukaryotic organisms. Recent studies have revealed the critical role of circRNAs in cancer progression. Yet, little is not well understood of hsa-circ-0064636 in osteosarcoma (OS).Methods: The differential expression of hsa-circ-0064636 in OS cell lines was verified by quantitative real-time PCR (qRT-PCR). Differentially expressed mRNAs and miRNAs were screened in OS mRNA and miRNA expression datasets. miRNAs that interacted with hsa-circ-0064636 were predicted by RNAhybrid, TargetScan and miRanda. and were further detected using RNAhybrid, TargetScan and miRanda. miRWalk, miRMap, and miRNAMap were used to perform target gene prediction on the intersected miRNAs to construct a circ-miRNA-mRNA interactor network. The target genes were then subjected to survival analysis using PROGgeneV2, which resulted in a circ-miRNA-mRNA interaction subnetwork with prognostic impact.Results: The qRT-PCR experiments successfully verified that hsa-circ-0064636 was significantly overexpressed in the OS cell line. Hsa-mir-326(miR-326) and hsa-mir-503-5p(miR-503-5p) are target miRNAs of hsa-circ-0064636 in the target genes obtained from the miR-326 and miR-503-5p screens. UBE4A and VDAC1 had a significant effect on prognosis. UBE4A is a target gene for miR-326, while VDAC1 is a target gene for miR-503-5p .Conclusion: hsa-circ-0064636 may be involved in OS development through acting as a sponge to inhibit miR-326 and miR-503-5p , thus regulating the expression of VDAC1 and UBE4A.

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Abiotic Stress in Plants; Stress Perception to Molecular Response and Role of Biotechnological Tools in Stress Resistance

Agronomy ◽

10.3390/agronomy11081579 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1579

Author(s):

Qari Muhammad Imran ◽

Noreen Falak ◽

Adil Hussain ◽

Bong-Gyu Mun ◽

Byung-Wook Yun

Keyword(s):

Abiotic Stress ◽

Abiotic Stresses ◽

Target Genes ◽

Global Scale ◽

Plant Production ◽

Signaling Cascades ◽

Molecular Response ◽

Rna Seq ◽

Stress Signal

Plants, due to their sessile nature, face several environmental adversities. Abiotic stresses such as heat, cold, drought, heavy metals, and salinity are serious threats to plant production and yield. To cope with these stresses, plants have developed sophisticated mechanisms to avoid or resist stress conditions. A proper response to abiotic stress depends primarily on how plants perceive the stress signal, which in turn leads to initiation of signaling cascades and induction of resistance genes. New biotechnological tools such as RNA-seq and CRISPR-cas9 are quite useful in identifying target genes on a global scale, manipulating these genes to achieve tolerance, and helping breeders to develop stress-tolerant cultivars. In this review, we will briefly discuss the adverse effects of key abiotic stresses such as cold, heat, drought, and salinity. We will also discuss how plants sense various stresses and the importance of biotechnological tools in the development of stress-tolerant cultivars.

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The Emerging Role of Suppressors of Cytokine Signaling (SOCS) in the Development and Progression of Leukemia

Cancers ◽

10.3390/cancers13164000 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4000

Author(s):

Esra’a Keewan ◽

Ksenia Matlawska-Wasowska

Keyword(s):

Intracellular Signaling ◽

Cell Communication ◽

Janus Kinase ◽

Signaling Cascades ◽

Cytokine Signaling ◽

Surface Receptors ◽

Wide Range ◽

Stat Signaling ◽

Leukemia Development

Cytokines are pleiotropic signaling molecules that execute an essential role in cell-to-cell communication through binding to cell surface receptors. Receptor binding activates intracellular signaling cascades in the target cell that bring about a wide range of cellular responses, including induction of cell proliferation, migration, differentiation, and apoptosis. The Janus kinase and transducers and activators of transcription (JAK/STAT) signaling pathways are activated upon cytokines and growth factors binding with their corresponding receptors. The SOCS family of proteins has emerged as a key regulator of cytokine signaling, and SOCS insufficiency leads to constitutive activation of JAK/STAT signaling and oncogenic transformation. Dysregulation of SOCS expression is linked to various solid tumors with invasive properties. However, the roles of SOCS in hematological malignancies, such as leukemia, are less clear. In this review, we discuss the recent advances pertaining to SOCS dysregulation in leukemia development and progression. We also highlight the roles of specific SOCS in immune cells within the tumor microenvironment and their possible involvement in anti-tumor immunity. Finally, we discuss the epigenetic, genetic, and post-transcriptional modifications of SOCS genes during tumorigenesis, with an emphasis on leukemia.

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