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Transcriptional Regulation: Molecules, Involved Mechanisms and Misregulation 2019

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 47444

Special Issue Editors


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Guest Editor
1. CNR, Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, Via Pietro Castellino, 111-80131 Naples, Italy
2. Department of Science and Technology, University of Naples “Parthenope", Centro Direzionale, Isola C4-800143, Naples, Italy
Interests: human genetic diseases; molecular mechanism pathogenesis; whole-transcriptome analysis; non-coding RNAs
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Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous special issue "Transcriptional Regulation: Molecules, Involved Mechanisms and Misregulation".

Transcriptional regulation of gene expression in response to intra- and extra-cellular changes includes a series of biophysical processes controlled by innumerable transcription factors, cofactors and chromatin regulators. This control involves multiple temporal and functional steps and levels ranging from specific DNA–protein interactions to the recruitment and assembly of nucleoprotein complexes. The huge amount of participating molecules, together with the complexity of the mechanism, constrains the use of novel strategies to fully understand how DNA sequence information, epigenetic modifications and transcription machinery cooperate to regulate gene expression. Recent advances in “omics” and computational biology have provided promising tools to reliably integrate different layers of information from biophysical, biochemical and molecular cell biology studies. Thus, this Special Issue is focused on the molecular mechanisms leading to specific gene expression patterns, with particular attention to molecules and complexes involved in transcription regulation. Especially, studies employing these novel integrated approaches will be considered as priority. Additionally, research papers and review articles exploring the effects of transcriptional misregulation on human diseases will be also included.

Dr. Amelia Casamassimi
Prof. Dr. Alfredo Ciccodicola
Dr. Monica Rienzo
Guest Editors

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Keywords

  • transcription machinery
  • nucleic acid-protein interactions
  • chromatin modifying complexes
  • molecular recognition
  • biomolecular interactions
  • posttranscriptional modifications
  • transcription misregulation
  • computational biophysics

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Published Papers (11 papers)

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19 pages, 6671 KiB  
Article
The ER Unfolded Protein Response Effector, ATF6, Reduces Cardiac Fibrosis and Decreases Activation of Cardiac Fibroblasts
by Winston T. Stauffer, Erik A. Blackwood, Khalid Azizi, Randal J. Kaufman and Christopher C. Glembotski
Int. J. Mol. Sci. 2020, 21(4), 1373; https://doi.org/10.3390/ijms21041373 - 18 Feb 2020
Cited by 17 | Viewed by 3919
Abstract
Activating transcription factor-6 α (ATF6) is one of the three main sensors and effectors of the endoplasmic reticulum (ER) stress response and, as such, it is critical for protecting the heart and other tissues from a variety of environmental insults and disease states. [...] Read more.
Activating transcription factor-6 α (ATF6) is one of the three main sensors and effectors of the endoplasmic reticulum (ER) stress response and, as such, it is critical for protecting the heart and other tissues from a variety of environmental insults and disease states. In the heart, ATF6 has been shown to protect cardiac myocytes. However, its roles in other cell types in the heart are unknown. Here we show that ATF6 decreases the activation of cardiac fibroblasts in response to the cytokine, transforming growth factor β (TGFβ), which can induce fibroblast trans-differentiation into a myofibroblast phenotype through signaling via the TGFβ–Smad pathway. ATF6 activation suppressed fibroblast contraction and the induction of α smooth muscle actin (αSMA). Conversely, fibroblasts were hyperactivated when ATF6 was silenced or deleted. ATF6 thus represents a novel inhibitor of the TGFβ–Smad axis of cardiac fibroblast activation. Full article
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14 pages, 4165 KiB  
Article
Disabling the Protease DDI2 Attenuates the Transcriptional Activity of NRF1 and Potentiates Proteasome Inhibitor Cytotoxicity
by Amy Northrop, Janakiram R. Vangala, Alex Feygin and Senthil K. Radhakrishnan
Int. J. Mol. Sci. 2020, 21(1), 327; https://doi.org/10.3390/ijms21010327 - 3 Jan 2020
Cited by 27 | Viewed by 5213
Abstract
Proteasome inhibition is used therapeutically to induce proteotoxic stress and trigger apoptosis in cancer cells that are highly dependent on the proteasome. As a mechanism of resistance, inhibition of the cellular proteasome induces the synthesis of new, uninhibited proteasomes to restore proteasome activity [...] Read more.
Proteasome inhibition is used therapeutically to induce proteotoxic stress and trigger apoptosis in cancer cells that are highly dependent on the proteasome. As a mechanism of resistance, inhibition of the cellular proteasome induces the synthesis of new, uninhibited proteasomes to restore proteasome activity and relieve proteotoxic stress in the cell, thus evading apoptosis. This evolutionarily conserved compensatory mechanism is referred to as the proteasome-bounce back response and is orchestrated in mammalian cells by nuclear factor erythroid derived 2-related factor 1 (NRF1), a transcription factor and master regulator of proteasome subunit genes. Upon synthesis, NRF1 is cotranslationally inserted into the endoplasmic reticulum (ER), then is rapidly retrotranslocated into the cytosol and degraded by the proteasome. In contrast, during conditions of proteasome inhibition or insufficiency, NRF1 escapes degradation, is proteolytically cleaved by the aspartyl protease DNA damage inducible 1 homolog 2 (DDI2) to its active form, and enters the nucleus as an active transcription factor. Despite these insights, the cellular compartment where the proteolytic processing step occurs remains unclear. Here we further probed this pathway and found that NRF1 can be completely retrotranslocated into the cytosol where it is then cleaved and activated by DDI2. Furthermore, using a triple-negative breast cancer cell line MDA-MB-231, we investigated the therapeutic utility of attenuating DDI2 function. We found that DDI2 depletion attenuated NRF1 activation and potentiated the cytotoxic effects of the proteasome inhibitor carfilzomib. More importantly, expression of a point-mutant of DDI2 that is protease-dead recapitulated these effects. Taken together, our results provide a strong rationale for a combinational therapy that utilizes inhibition of the proteasome and the protease function of DDI2. This approach could expand the repertoire of cancer types that can be successfully treated with proteasome inhibitors in the clinic. Full article
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22 pages, 4782 KiB  
Article
Genome-Wide Analysis of the FABP Gene Family in Liver of Chicken (Gallus gallus): Identification, Dynamic Expression Profile, and Regulatory Mechanism
by Zhang Wang, Ya-Xin Yue, Zi-Ming Liu, Li-Yu Yang, Hong Li, Zhuan-Jian Li, Guo-Xi Li, Yan-Bin Wang, Ya-Dong Tian, Xiang-Tao Kang and Xiao-Jun Liu
Int. J. Mol. Sci. 2019, 20(23), 5948; https://doi.org/10.3390/ijms20235948 - 26 Nov 2019
Cited by 18 | Viewed by 4230
Abstract
The fatty acid-binding protein (FABP) gene family, which encodes a group of fatty acid-trafficking molecules that affect cellular functions, has been studied extensively in mammals. However, little is known about the gene structure, expression profile, and regulatory mechanism of the gene [...] Read more.
The fatty acid-binding protein (FABP) gene family, which encodes a group of fatty acid-trafficking molecules that affect cellular functions, has been studied extensively in mammals. However, little is known about the gene structure, expression profile, and regulatory mechanism of the gene family in chickens. In the present study, bioinformatics-based methods were used to identify the family members and investigate their evolutionary history and features of gene structure. Real-time PCR combined with in vivo and in vitro experiments were used to examine the spatiotemporal expression pattern, and explore the regulatory mechanism of FABP genes. The results show that nine members of the FABP gene family, which branched into two clusters and shared a conserved FATTYACIDBP domain, exist in the genome of chickens. Of these, seven FABP genes, including FABP1, FABP3-7, and FABP10 were abundantly expressed in the liver of hens. The expression levels of FABP1, FABP3, and FABP10 were significantly increased, FABP5 and FABP7 were significantly decreased, and FABP4 and FABP6 remained unchanged in hens at the peak laying stage in comparison to those at the pre-laying stage. Transcription of FABP1 and FABP3 were activated by estrogen via estrogen receptor (ER) α, whilst FABP10 was activated by estrogen via ERβ. Meanwhile, the expression of FABP1 was regulated by peroxisome proliferator activated receptor (PPAR) isoforms, of which tested PPARα and PPARβ agonists significantly inhibited the expression of FABP1, while tested PPARγ agonists significantly increased the expression of FABP1, but downregulated it when the concentration of the PPARγ agonist reached 100 nM. The expression of FABP3 was upregulated via tested PPARβ and PPARγ agonists, and the expression of FABP7 was selectively promoted via PPARγ. The expression of FABP10 was activated by all of the three tested PPAR agonists, but the expression of FABP4-6 was not affected by any of the PPAR agonists. In conclusion, members of the FABP gene family in chickens shared similar functional domains, gene structures, and evolutionary histories with mammalian species, but exhibited varying expression profiles and regulatory mechanisms. The results provide a valuable resource for better understanding the biological functions of individual FABP genes in chickens. Full article
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16 pages, 2683 KiB  
Article
Comparative Analysis of the Characteristics of Triterpenoid Transcriptome from Different Strains of Wolfiporia cocos
by Guiping Zeng, Zhong Li and Zhi Zhao
Int. J. Mol. Sci. 2019, 20(15), 3703; https://doi.org/10.3390/ijms20153703 - 29 Jul 2019
Cited by 8 | Viewed by 3029
Abstract
The dried sclerotia of Wolfiporia cocos (Schwein.) Ryvarden & Gilb., a traditional Chinese medicine, has triterpenoid as its main active component. Breeding high-yield triterpenoid in W. cocos is an important research topic at present. We screened out two monosporal strains from the same [...] Read more.
The dried sclerotia of Wolfiporia cocos (Schwein.) Ryvarden & Gilb., a traditional Chinese medicine, has triterpenoid as its main active component. Breeding high-yield triterpenoid in W. cocos is an important research topic at present. We screened out two monosporal strains from the same W. cocos 5.78, high-yielding DZAC-Wp-H-29 (H) and low-yielding DZAC-Wp-L-123 (L), and cultured mycelia for 17 days, 34 days, and 51 days, respectively. Transcriptome analysis results showed that triterpenoid synthesis is closely related to gene expression in triterpenoid synthesis pathways (hydroxymethyl glutaryl-CoA reductase (HMGCR), farnesyl diphosphate synthase (FDPS), 4-hydroxybenzoate polyprenyltransferase (COQ2), C-8 sterol isomerase (ERG2), sterol O-acyltransferase (ACAT), tyrosine aminotransferase (TAT), torulene dioxygenase (CAO2), and sterol-4alpha-carboxylate 3-dehydrogenase (erg26)), and is limited by the expression of enzyme M20 combined with domain protein peptide (Pm20d2), aryl-alcohol dehydrogenase (norA), ISWI chromatin-remodeling complex ATPase ISW2, GroES-like protein (adh), cytochrome P450 (ftmP450-1), and unknown proteins unigene0001029 and unigene0011374. In addition, maintaining high triterpenoid accumulation in W. cocos may require a stable membrane structure, so the accumulation ability may be related to the high synthesis ability of sterols. The low accumulation of triterpenoid in W. cocos may be due to the products of key enzymes increasing flow to other pathways. Full article
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14 pages, 2805 KiB  
Article
Transcriptional Regulation of gga-miR-451 by AhR:Arnt in Mycoplasma gallisepticum (HS Strain) Infection
by Yabo Zhao, Yali Fu, Yingfei Sun, Mengyun Zou and Xiuli Peng
Int. J. Mol. Sci. 2019, 20(12), 3087; https://doi.org/10.3390/ijms20123087 - 24 Jun 2019
Cited by 11 | Viewed by 3130
Abstract
MicroRNAs (miRNAs) have been determined to be important regulators for pathogenic microorganism infection. However, it is largely unclear how miRNAs are triggered during pathogen infection. We previously reported that the up-regulation of gga-miR-451 negatively regulates the Mycoplasma gallisepticum (MG)-induced production of inflammatory cytokines [...] Read more.
MicroRNAs (miRNAs) have been determined to be important regulators for pathogenic microorganism infection. However, it is largely unclear how miRNAs are triggered during pathogen infection. We previously reported that the up-regulation of gga-miR-451 negatively regulates the Mycoplasma gallisepticum (MG)-induced production of inflammatory cytokines via targeting tyrosine3-monooxygenase/tryptophan5-monooxygenase activation protein zeta (YWHAZ). The aim of this study was to investigate the mechanism regulating gga-miR-451 in MG infection in chickens. Analysis of gga-miR-451 precursor, pri-miR-451, and pre-miR-451 indicated that the regulation occurred transcriptionally. We also identified the transcriptional regulatory region of gga-miR-451 that contained consensus-binding motif for aryl hydrocarbon receptor (AhR) and aryl hydrocarbon receptor nuclear translocator (Arnt) complex, which is known as the transcription factor that regulates gene expression. Luciferase reporter assays combined with chromatin immunoprecipitation (ChIP) demonstrated that AhR:Arnt bound directly to the promoter elements of gga-miR-451, which were responsible for gga-miR-451 transcription in the context of MG infection. Furthermore, upregulation of AhR:Arnt significantly induced gga-miR-451 and inhibited YWHAZ expression, suggesting that AhR:Arnt may play an anti-inflammatory role in MG infection. This discovery suggests that induced gga-miR-451 expression is modulated by AhR:Arnt in response to MG infection. Full article
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16 pages, 9252 KiB  
Article
Analysis of the microRNA Expression Profile of Bovine Monocyte-derived Macrophages Infected with Mycobacterium avium subsp. Paratuberculosis Reveals that miR-150 Suppresses Cell Apoptosis by Targeting PDCD4
by Zi Wang, Ling Cong Kong, Bo Yan Jia, Jing Rui Chen, Yang Dong, Xiu Yun Jiang and Hong Xia Ma
Int. J. Mol. Sci. 2019, 20(11), 2708; https://doi.org/10.3390/ijms20112708 - 1 Jun 2019
Cited by 16 | Viewed by 3622
Abstract
M. avium subsp. paratuberculosis (MAP) is the causative pathogen of Johne’s disease, a chronic granulomatous enteritis that principally affects ruminants and can survive, proliferate and disseminate in macrophages. MicroRNAs (miRNAs) are important regulators of gene expression and can impact the processes [...] Read more.
M. avium subsp. paratuberculosis (MAP) is the causative pathogen of Johne’s disease, a chronic granulomatous enteritis that principally affects ruminants and can survive, proliferate and disseminate in macrophages. MicroRNAs (miRNAs) are important regulators of gene expression and can impact the processes of cells. To investigate the role of miRNAs in monocyte-derived macrophages (MDMs) during MAP infection, we used high-throughput sequencing technology to analyze small RNA libraries of MAP-infected and control MDMs. The results showed that a total of 21 miRNAs were differentially expressed in MDMs after MAP infection, and 8864 target genes were predicted. A functional analysis showed that the target genes were mainly involved in the MAPK signaling pathway, Toll-like receptor signaling pathway, NF-kappa B signaling pathway and apoptosis. In addition, using a dual-luciferase reporter assay, flow cytometry, and a small interfering (si)RNA knockdown assay, the role of miR-150 in regulating macrophage apoptosis by targeting the programmed cell death protein-4 (PDCD4) was demonstrated. These results provide an experimental basis to reveal the regulatory mechanism of MAP infection and suggest the potential of miRNAs as biomarkers for the diagnosis of Johne’s disease in bovines. Full article
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13 pages, 1824 KiB  
Article
Identification and Characterization of Novel Fusion Genes with Potential Clinical Applications in Mexican Children with Acute Lymphoblastic Leukemia
by Minerva Mata-Rocha, Angelica Rangel-López, Elva Jiménez-Hernández, Blanca Angélica Morales-Castillo, Carolina González-Torres, Javier Gaytan-Cervantes, Enrique Álvarez-Olmos, Juan Carlos Núñez-Enríquez, Arturo Fajardo-Gutiérrez, Jorge Alfonso Martín-Trejo, Karina Anastacia Solís-Labastida, Aurora Medina-Sansón, Janet Flores-Lujano, Omar Alejandro Sepúlveda-Robles, José Gabriel Peñaloza-González, Laura Eugenia Espinoza-Hernández, Nora Nancy Núñez-Villegas, Rosa Martha Espinosa-Elizondo, Beatriz Cortés-Herrera, José Refugio Torres-Nava, Luz Victoria Flores-Villegas, Laura Elizabeth Merino-Pasaye, Vilma Carolina Bekker-Méndez, Martha Margarita Velázquez-Aviña, María Luisa Pérez-Saldívar, Benito Alejandro Bautista-Martínez, Raquel Amador-Sánchez, Ana Itamar González-Avila, Silvia Jiménez-Morales, David Aldebarán Duarte-Rodríguez, Jessica Denisse Santillán-Juárez, Alejandra Jimena García-Velázquez, Haydeé Rosas-Vargas and Juan Manuel Mejía-Aranguréadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2019, 20(10), 2394; https://doi.org/10.3390/ijms20102394 - 15 May 2019
Cited by 14 | Viewed by 5917
Abstract
Acute lymphoblastic leukemia is the most common type of childhood cancer worldwide. Mexico City has one of the highest incidences and mortality rates of this cancer. It has previously been recognized that chromosomal translocations are important in cancer etiology. Specific fusion genes have [...] Read more.
Acute lymphoblastic leukemia is the most common type of childhood cancer worldwide. Mexico City has one of the highest incidences and mortality rates of this cancer. It has previously been recognized that chromosomal translocations are important in cancer etiology. Specific fusion genes have been considered as important treatment targets in childhood acute lymphoblastic leukemia (ALL). The present research aimed at the identification and characterization of novel fusion genes with potential clinical implications in Mexican children with acute lymphoblastic leukemia. The RNA-sequencing approach was used. Four fusion genes not previously reported were identified: CREBBP-SRGAP2B, DNAH14-IKZF1, ETV6-SNUPN, ETV6-NUFIP1. Although a fusion gene is not sufficient to cause leukemia, it could be involved in the pathogenesis of the disease. Notably, these new translocations were found in genes encoding for hematopoietic transcription factors which are known to play an important role in leukemogenesis and disease prognosis such as IKZF1, CREBBP, and ETV6. In addition, they may have an impact on the prognosis of Mexican pediatric patients with ALL, with the potential to be included in the current risk stratification schemes or used as therapeutic targets. Full article
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14 pages, 4234 KiB  
Article
Hypoxia-Regulated miRNAs in Human Mesenchymal Stem Cells: Exploring the Regulatory Effects in Ischemic Disorders
by Carmela Dell’Aversana, Francesca Cuomo, Chiara Botti, Ciro Maione, Annamaria Carissimo, Amelia Casamassimi, Lucia Altucci and Gilda Cobellis
Int. J. Mol. Sci. 2019, 20(6), 1340; https://doi.org/10.3390/ijms20061340 - 16 Mar 2019
Cited by 3 | Viewed by 2885
Abstract
Human mesenchymal/stromal stem cells (hMSC) are the most promising cell source for adult cell therapies in regenerative medicine. Many clinical trials have reported the use of autologous transplantation of hMSCs in several disorders, but with limited results. To exert their potential, hMSCs could [...] Read more.
Human mesenchymal/stromal stem cells (hMSC) are the most promising cell source for adult cell therapies in regenerative medicine. Many clinical trials have reported the use of autologous transplantation of hMSCs in several disorders, but with limited results. To exert their potential, hMSCs could exhibit efficient homing and migration toward lesion sites among other effects, but the underlying process is not clear enough. To further increase the knowledge, we studied the co-regulation between hypoxia-regulated genes and miRNAs. To this end, we investigated the miRNA expression profile of healthy hMSCs in low oxygen/nutrient conditions to mimic ischemia and compared with cells of patients suffering from critical limb ischemia (CLI). miRNAs are small, highly conserved, non-coding RNAs, skilled in the control of the target’s expression level in a fine-tuned way. After analyzing the miRNOme in CLI-derived hMSC cells and healthy controls, and intersecting the results with the mRNA expression dataset under hypoxic conditions, we identified two miRNAs potentially relevant to the disease: miR-29b as a pathological marker of the disease and miR-638 as a therapeutic target. This study yielded a deeper understanding of stem cell biology and ischemic disorders, opening new potential treatments in the future. Full article
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19 pages, 1765 KiB  
Article
Identification of GA-Binding Protein Transcription Factor Alpha Subunit (GABPA) as a Novel Bookmarking Factor
by Shunya Goto, Masashi Takahashi, Narumi Yasutsune, Sumiki Inayama, Dai Kato, Masashi Fukuoka, Shu-ichiro Kashiwaba and Yasufumi Murakami
Int. J. Mol. Sci. 2019, 20(5), 1093; https://doi.org/10.3390/ijms20051093 - 4 Mar 2019
Cited by 5 | Viewed by 4097
Abstract
Mitotic bookmarking constitutes a mechanism for transmitting transcriptional patterns through cell division. Bookmarking factors, comprising a subset of transcription factors (TFs), and multiple histone modifications retained in mitotic chromatin facilitate reactivation of transcription in the early G1 phase. However, the specific TFs that [...] Read more.
Mitotic bookmarking constitutes a mechanism for transmitting transcriptional patterns through cell division. Bookmarking factors, comprising a subset of transcription factors (TFs), and multiple histone modifications retained in mitotic chromatin facilitate reactivation of transcription in the early G1 phase. However, the specific TFs that act as bookmarking factors remain largely unknown. Previously, we identified the “early G1 genes” and screened TFs that were predicted to bind to the upstream region of these genes, then identified GA-binding protein transcription factor alpha subunit (GABPA) and Sp1 transcription factor (SP1) as candidate bookmarking factors. Here we show that GABPA and multiple histone acetylation marks such as H3K9/14AC, H3K27AC, and H4K5AC are maintained at specific genomic sites in mitosis. During the M/G1 transition, the levels of these histone acetylations at the upstream regions of genes bound by GABPA in mitosis are decreased. Upon depletion of GABPA, levels of histone acetylation, especially H4K5AC, at several gene regions are increased, along with transcriptional induction at 1 h after release. Therefore, we proposed that GABPA cooperates with the states of histone acetylation to act as a novel bookmarking factor which, may negatively regulate transcription during the early G1 phase. Full article
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Review

Jump to: Research

17 pages, 3347 KiB  
Review
Sledgehammer to Scalpel: Broad Challenges to the Heart and Other Tissues Yield Specific Cellular Responses via Transcriptional Regulation of the ER-Stress Master Regulator ATF6α
by Winston T. Stauffer, Adrian Arrieta, Erik A. Blackwood and Christopher C. Glembotski
Int. J. Mol. Sci. 2020, 21(3), 1134; https://doi.org/10.3390/ijms21031134 - 8 Feb 2020
Cited by 9 | Viewed by 4308
Abstract
There are more than 2000 transcription factors in eukaryotes, many of which are subject to complex mechanisms fine-tuning their activity and their transcriptional programs to meet the vast array of conditions under which cells must adapt to thrive and survive. For example, conditions [...] Read more.
There are more than 2000 transcription factors in eukaryotes, many of which are subject to complex mechanisms fine-tuning their activity and their transcriptional programs to meet the vast array of conditions under which cells must adapt to thrive and survive. For example, conditions that impair protein folding in the endoplasmic reticulum (ER), sometimes called ER stress, elicit the relocation of the ER-transmembrane protein, activating transcription factor 6α (ATF6α), to the Golgi, where it is proteolytically cleaved. This generates a fragment of ATF6α that translocates to the nucleus, where it regulates numerous genes that restore ER protein-folding capacity but is degraded soon after. Thus, upon ER stress, ATF6α is converted from a stable, transmembrane protein, to a rapidly degraded, nuclear protein that is a potent transcription factor. This review focuses on the molecular mechanisms governing ATF6α location, activity, and stability, as well as the transcriptional programs ATF6α regulates, whether canonical genes that restore ER protein-folding or unexpected, non-canonical genes affecting cellular functions beyond the ER. Moreover, we will review fascinating roles for an ATF6α isoform, ATF6β, which has a similar mode of activation but, unlike ATF6α, is a long-lived, weak transcription factor that may moderate the genetic effects of ATF6α. Full article
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22 pages, 2217 KiB  
Review
The Roles of FoxO Transcription Factors in Regulation of Bone Cells Function
by Xiaoli Ma, Peihong Su, Chong Yin, Xiao Lin, Xue Wang, Yongguang Gao, Suryaji Patil, Abdul Rouf War, Abdul Qadir, Ye Tian and Airong Qian
Int. J. Mol. Sci. 2020, 21(3), 692; https://doi.org/10.3390/ijms21030692 - 21 Jan 2020
Cited by 69 | Viewed by 6323
Abstract
Forkhead box class O family member proteins (FoxOs) are evolutionarily conserved transcription factors for their highly conserved DNA-binding domain. In mammalian species, all the four FoxO members, FoxO1, FoxO3, FoxO4, and FoxO6, are expressed in different organs. In bone, the first three members [...] Read more.
Forkhead box class O family member proteins (FoxOs) are evolutionarily conserved transcription factors for their highly conserved DNA-binding domain. In mammalian species, all the four FoxO members, FoxO1, FoxO3, FoxO4, and FoxO6, are expressed in different organs. In bone, the first three members are extensively expressed and more studied. Bone development, remodeling, and homeostasis are all regulated by multiple cell lineages, including osteoprogenitor cells, chondrocytes, osteoblasts, osteocytes, osteoclast progenitors, osteoclasts, and the intercellular signaling among these bone cells. The disordered FoxOs function in these bone cells contribute to osteoarthritis, osteoporosis, or other bone diseases. Here, we review the current literature of FoxOs for their roles in bone cells, focusing on helping researchers to develop new therapeutic approaches and prevent or treat the related bone diseases. Full article
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