scholarly journals SFPQ rescues F508del-CFTR expression and function in cystic fibrosis bronchial epithelial cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Parameet Kumar ◽  
Dharmendra Kumar Soni ◽  
Chaitali Sen ◽  
Mads B. Larsen ◽  
Krystyna Mazan-Mamczarz ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Lung Epithelial Cells ◽  
Regulation Of Expression ◽  
Trafficking Defects ◽  
And Function

AbstractCystic fibrosis (CF) occurs as a result of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which lead to misfolding, trafficking defects, and impaired function of the CFTR protein. Splicing factor proline/glutamine-rich (SFPQ) is a multifunctional nuclear RNA-binding protein (RBP) implicated in the regulation of gene expression pathways and intracellular trafficking. Here, we investigated the role of SFPQ in the regulation of the expression and function of F508del-CFTR in CF lung epithelial cells. We find that the expression of SFPQ is reduced in F508del-CFTR CF epithelial cells compared to WT-CFTR control cells. Interestingly, the overexpression of SFPQ in CF cells increases the expression as well as rescues the function of F508del-CFTR. Further, comprehensive transcriptome analyses indicate that SFPQ plays a key role in activating the mutant F508del-CFTR by modulating several cellular signaling pathways. This is the first report on the role of SFPQ in the regulation of expression and function of F508del-CFTR in CF lung disease. Our findings provide new insights into SFPQ-mediated molecular mechanisms and point to possible novel epigenetic therapeutic targets for CF and related pulmonary diseases.

scholarly journals SFPQ Rescues F508del-CFTR Expression and Function in Cystic Fibrosis Bronchial Epithelial Cells

2021 ◽  
Author(s):  
Parameet Kumar ◽  
Dharmendra Kumar Soni ◽  
Chaitali Sen ◽  
Mads B Larsen ◽  
Krystyna Mazan-Mamczarz ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Lung Epithelial Cells ◽  
Regulation Of Expression ◽  
Trafficking Defects ◽  
And Function

Abstract Cystic Fibrosis (CF) occurs as a result of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which lead to misfolding, trafficking defects, and impaired function of the CFTR protein. Splicing factor proline/glutamine-rich (SFPQ) is a multifunctional nuclear RNA-binding protein (RBP) implicated in the regulation of gene expression pathways and intracellular trafficking. Here, we investigated the role of SFPQ in the regulation of the expression and function of F508del-CFTR in CF lung epithelial cells. We find that the expression of SFPQ is reduced in F508del-CFTR CF epithelial cells compared to WT-CFTR control cells. Interestingly, the overexpression of SFPQ in CF cells increases the expression as well as rescues the function of F508del-CFTR. Further, comprehensive transcriptome analyses indicate that SFPQ plays a key role in activating the mutant F508del-CFTR by modulating several cellular signaling pathways. This is the first report on the role of SFPQ in the regulation of expression and function of F508del-CFTR in CF lung disease. Our findings provide new insights into SFPQ-mediated molecular mechanisms and point to possible novel epigenetic therapeutic targets for CF and related pulmonary diseases.

scholarly journals The Role of Translation Initiation Regulation in Haematopoiesis

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Godfrey Grech ◽  
Marieke von Lindern
Keyword(s):  
Gene Expression ◽  
Translation Initiation ◽  
Translational Control ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Translation Control ◽  
Haematological Disorders

Organisation of RNAs into functional subgroups that are translated in response to extrinsic and intrinsic factors underlines a relatively unexplored gene expression modulation that drives cell fate in the same manner as regulation of the transcriptome by transcription factors. Recent studies on the molecular mechanisms of inflammatory responses and haematological disorders indicate clearly that the regulation of mRNA translation at the level of translation initiation, mRNA stability, and protein isoform synthesis is implicated in the tight regulation of gene expression. This paper outlines how these posttranscriptional control mechanisms, including control at the level of translation initiation factors and the role of RNA binding proteins, affect hematopoiesis. The clinical relevance of these mechanisms in haematological disorders indicates clearly the potential therapeutic implications and the need of molecular tools that allow measurement at the level of translational control. Although the importance of miRNAs in translation control is well recognised and studied extensively, this paper will exclude detailed account of this level of control.

Regulation of miR-155 biogenesis in cystic fibrosis lung epithelial cells: Antagonistic role of two mRNA-destabilizing proteins, KSRP and TTP

2013 ◽  
Vol 433 (4) ◽  
pp. 484-488 ◽  
Author(s):  
Sharmistha Bhattacharyya ◽  
Parameet Kumar ◽  
Motohiro Tsuchiya ◽  
Anirban Bhattacharyya ◽  
Roopa Biswas
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Cystic Fibrosis Lung ◽  
Lung Epithelial

scholarly journals Revisiting Cell Death Responses in Fibrotic Lung Disease: Crosstalk between Structured and Non-Structured Cells

Diagnostics ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 504
Author(s):  
Kiyoharu Fukushima ◽  
Takashi Satoh ◽  
Hiroshi Kida ◽  
Atsushi Kumanogoh
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Immune Cells ◽  
Lung Fibrosis ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Cell Types ◽  
Lung Epithelial Cells ◽  
Binding Motif ◽  
Autoantibody Production

Fibrosis is a life-threatening disorder caused by excessive formation of connective tissue that can affect several critical organs. Innate immune cells are involved in the development of various disorders, including lung fibrosis. To date, several hematopoietic cell types have been implicated in fibrosis, including pro-fibrotic monocytes like fibrocytes and segregated-nucleus-containing atypical monocytes (SatMs), but the precise cellular and molecular mechanisms underlying its development remain unclear. Repetitive injury and subsequent cell death response are triggering events for lung fibrosis development. Crosstalk between lung structured and non-structured cells is known to regulate the key molecular event. We recently reported that RNA-binding motif protein 7 (RBM7) expression is highly upregulated in the fibrotic lung and plays fundamental roles in fibrosis development. RBM7 regulates nuclear degradation of NEAT1 non-coding RNA, resulting in sustained apoptosis in the lung epithelium and fibrosis. Apoptotic epithelial cells produce CXCL12, which leads to the recruitment of pro-fibrotic monocytes. Apoptosis is also the main source of autoantigens. Recent studies have revealed important functions for natural autoantibodies that react with specific sets of self-antigens and are unique to individual diseases. Here, we review recent insights into lung fibrosis development in association with crosstalk between structured cells like lung epithelial cells and non-structured cells like migrating immune cells, and discuss their relevance to acquired immunity through natural autoantibody production.

scholarly journals Role of epithelial sodium channels in the regulation of lung fluid homeostasis

2015 ◽  
Vol 309 (11) ◽  
pp. L1229-L1238 ◽  
Author(s):  
Sadis Matalon ◽  
Rafal Bartoszewski ◽  
James F. Collawn
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Fetal Lung ◽  
Airway Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Airway Epithelial ◽  
Lung Fluid ◽  
Lung Epithelial ◽  
Distal Lung

In utero, fetal lung epithelial cells actively secrete Cl− ions into the lung air spaces while Na+ ions follow passively to maintain electroneutrality. This process, driven by an electrochemical gradient generated by the Na+-K+-ATPase, is responsible for the secretion of fetal fluid that is essential for normal lung development. Shortly before birth, a significant upregulation of amiloride-sensitive epithelial channels (ENaCs) on the apical side of the lung epithelial cells results in upregulation of active Na+ transport. This process is critical for the reabsorption of fetal lung fluid and the establishment of optimum gas exchange. In the adult lung, active Na+ reabsorption across distal lung epithelial cells limits the degree of alveolar edema in patients with acute lung injury and cardiogenic edema. Cl− ions are transported either paracellularly or transcellularly to preserve electroneutrality. An increase in Cl− secretion across the distal lung epithelium has been reported following an acute increase in left atrial pressure and may result in pulmonary edema. In contrast, airway epithelial cells secrete Cl− through apical cystic fibrosis transmembrane conductance regulator and Ca2+-activated Cl− channels and absorb Na+. Thus the coordinated action of Cl− secretion and Na+ absorption is essential for maintenance of the volume of epithelial lining fluid that, in turn, maximizes mucociliary clearance and facilitates clearance of bacteria and debris from the lungs. Any factor that interferes with Na+ or Cl− transport or dramatically upregulates ENaC activity in airway epithelial cells has been associated with lung diseases such as cystic fibrosis or chronic obstructive lung disease. In this review we focus on the role of the ENaC, the mechanisms involved in ENaC regulation, and how ENaC dysregulation can lead to lung pathology.

scholarly journals NHERF1 and CFTR restore tight junction organisation and function in cystic fibrosis airway epithelial cells: role of ezrin and the RhoA/ROCK pathway

2012 ◽  
Vol 92 (11) ◽  
pp. 1527-1540 ◽  
Author(s):  
Stefano Castellani ◽  
Lorenzo Guerra ◽  
Maria Favia ◽  
Sante Di Gioia ◽  
Valeria Casavola ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Tight Junction ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Cystic Fibrosis Airway ◽  
And Function

NOB1: A Potential Biomarker or Target in Cancer

2019 ◽  
Vol 20 (10) ◽  
pp. 1081-1089
Author(s):  
Weiwei Ke ◽  
Zaiming Lu ◽  
Xiangxuan Zhao
Keyword(s):  
Cancer Treatment ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Binding Protein ◽  
Tumor Development ◽  
Anticancer Therapy ◽  
Research Progress ◽  
Normal Tissues ◽  
Potential Biomarker

Human NIN1/RPN12 binding protein 1 homolog (NOB1), an RNA binding protein, is expressed ubiquitously in normal tissues such as the lung, liver, and spleen. Its core physiological function is to regulate protease activities and participate in maintaining RNA metabolism and stability. NOB1 is overexpressed in a variety of cancers, including pancreatic cancer, non-small cell lung cancer, ovarian cancer, prostate carcinoma, osteosarcoma, papillary thyroid carcinoma, colorectal cancer, and glioma. Although existing data indicate that NOB1 overexpression is associated with cancer growth, invasion, and poor prognosis, the molecular mechanisms behind these effects and its exact roles remain unclear. Several studies have confirmed that NOB1 is clinically relevant in different cancers, and further research at the molecular level will help evaluate the role of NOB1 in tumors. NOB1 has become an attractive target in anticancer therapy because it is overexpressed in many cancers and mediates different stages of tumor development. Elucidating the role of NOB1 in different signaling pathways as a potential cancer treatment will provide new ideas for existing cancer treatment methods. This review summarizes the research progress made into NOB1 in cancer in the past decade; this information provides valuable clues and theoretical guidance for future anticancer therapy by targeting NOB1.

MC1568 inhibits HDAC6/8 activity and influenza A virus replication in lung epithelial cells: role of Hsp90 acetylation

2016 ◽  
Vol 8 (17) ◽  
pp. 2017-2031 ◽  
Author(s):  
Simona Panella ◽  
Maria Elena Marcocci ◽  
Ignacio Celestino ◽  
Sergio Valente ◽  
Clemens Zwergel ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Influenza A Virus ◽  
Virus Replication ◽  
Influenza A ◽  
Lung Epithelial Cells ◽  
Lung Epithelial

scholarly journals Pseudogene ACTBP2 increases blood–brain barrier permeability by promoting KHDRBS2 transcription through recruitment of KMT2D/WDR5 in Aβ1–42 microenvironment

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qianshuo Liu ◽  
Xiaobai Liu ◽  
Defeng Zhao ◽  
Xuelei Ruan ◽  
Rui Su ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Vital Role ◽  
Brain Barrier ◽  
Blood Brain ◽  
Bbb Permeability ◽  
Novel Target ◽  
And Function

AbstractThe blood–brain barrier (BBB) has a vital role in maintaining the homeostasis of the central nervous system (CNS). Changes in the structure and function of BBB can accelerate Alzheimer’s disease (AD) development. β-Amyloid (Aβ) deposition is the major pathological event of AD. We elucidated the function and possible molecular mechanisms of the effect of pseudogene ACTBP2 on the permeability of BBB in Aβ1–42 microenvironment. BBB model treated with Aβ1–42 for 48 h were used to simulate Aβ-mediated BBB dysfunction in AD. We proved that pseudogene ACTBP2, RNA-binding protein KHDRBS2, and transcription factor HEY2 are highly expressed in ECs that were obtained in a BBB model in vitro in Aβ1–42 microenvironment. In Aβ1–42-incubated ECs, ACTBP2 recruits methyltransferases KMT2D and WDR5, binds to KHDRBS2 promoter, and promotes KHDRBS2 transcription. The interaction of KHDRBS2 with the 3′UTR of HEY2 mRNA increases the stability of HEY2 and promotes its expression. HEY2 increases BBB permeability in Aβ1–42 microenvironment by transcriptionally inhibiting the expression of ZO-1, occludin, and claudin-5. We confirmed that knocking down of Khdrbs2 or Hey2 increased the expression levels of ZO-1, occludin, and claudin-5 in APP/PS1 mice brain microvessels. ACTBP2/KHDRBS2/HEY2 axis has a crucial role in the regulation of BBB permeability in Aβ1–42 microenvironment, which may provide a novel target for the therapy of AD.

scholarly journals The control of inflammation via the phosphorylation and dephosphorylation of tristetraprolin: a tale of two phosphatases

2016 ◽  
Vol 44 (5) ◽  
pp. 1321-1337 ◽  
Author(s):  
Andrew R. Clark ◽  
Jonathan L.E. Dean
Keyword(s):  
Inflammatory Mediators ◽  
Knockout Mouse ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Human Orthologue ◽  
And Function ◽  
Detailed Picture ◽  
Lines Of Evidence

Twenty years ago, the first description of a tristetraprolin (TTP) knockout mouse highlighted the fundamental role of TTP in the restraint of inflammation. Since then, work from several groups has generated a detailed picture of the expression and function of TTP. It is a sequence-specific RNA-binding protein that orchestrates the deadenylation and degradation of several mRNAs encoding inflammatory mediators. It is very extensively post-translationally modified, with more than 30 phosphorylations that are supported by at least two independent lines of evidence. The phosphorylation of two particular residues, serines 52 and 178 of mouse TTP (serines 60 and 186 of the human orthologue), has profound effects on the expression, function and localisation of TTP. Here, we discuss the control of TTP biology via its phosphorylation and dephosphorylation, with a particular focus on recent advances and on questions that remain unanswered.

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