scholarly journals KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1607 ◽  
Author(s):  
Luis Sousa ◽  
Ines Pankonien ◽  
Luka A Clarke ◽  
Iris Silva ◽  
Karl Kunzelmann ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Anion Channel ◽  
Stem Cell Differentiation ◽  
Epithelial Differentiation ◽  
Negative Regulator ◽  
Main Function ◽  
Serine Threonine Kinase ◽  
Cf Transmembrane Conductance Regulator ◽  
Differentiation And Proliferation ◽  
And Function

Cystic Fibrosis (CF) is caused by >2000 mutations in the CF transmembrane conductance regulator (CFTR) gene, but one mutation—F508del—occurs in ~80% of patients worldwide. Besides its main function as an anion channel, the CFTR protein has been implicated in epithelial differentiation, tissue regeneration, and, when dysfunctional, cancer. However, the mechanisms that regulate such relationships are not fully elucidated. Krüppel-like factors (KLFs) are a family of transcription factors (TFs) playing central roles in development, stem cell differentiation, and proliferation. Herein, we hypothesized that these TFs might have an impact on CFTR expression and function, being its missing link to differentiation. Our results indicate that KLF4 (but not KLF2 nor KLF5) is upregulated in CF vs. non-CF cells and that it negatively regulates wt-CFTR expression and function. Of note, F508del–CFTR expressing cells are insensitive to KLF4 modulation. Next, we investigated which KLF4-related pathways have an effect on CFTR. Our data also show that KLF4 modulates wt-CFTR (but not F508del–CFTR) via both the serine/threonine kinase AKT1 (AKT) and glycogen synthase kinase 3 beta (GSK3β) signaling. While AKT acts positively, GSK3β is a negative regulator of CFTR. This crosstalk between wt-CFTR and KLF4 via AKT/ GSK3β signaling, which is disrupted in CF, constitutes a novel mechanism linking CFTR to the epithelial differentiation.

scholarly journals Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles

2019 ◽  
Vol 5 (2) ◽  
pp. 00082-2019 ◽  
Author(s):  
Jennifer L. Taylor-Cousar ◽  
Marcus A. Mall ◽  
Bonnie W. Ramsey ◽  
Edward F. McKone ◽  
Elizabeth Tullis ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Anion Channel ◽  
Triple Combination ◽  
Open Label ◽  
Cftr Protein ◽  
Trafficking Defects ◽  
Cf Transmembrane Conductance Regulator ◽  
And Function ◽  
Cftr Modulators

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (CFTR) that result in diminished quantity and/or function of the CFTR anion channel. F508del-CFTR, the most common CF-causing mutation (found in ∼90% of patients), causes severe processing and trafficking defects, resulting in decreased CFTR quantity and function. CFTR modulators are medications that increase the amount of mature CFTR protein (correctors) or enhance channel function (potentiators) at the cell surface.Combinations of CFTR correctors and potentiators (i.e. lumacaftor/ivacaftor, tezacaftor/ivacaftor) have demonstrated clinical benefit in subsets of patients. However, none are approved for patients with CF heterozygous for F508del-CFTR and a minimal function mutation, i.e. a mutation that produces either no protein or protein that is unresponsive to currently approved CFTR modulators. Next-generation CFTR correctors VX-659 and VX-445, each in triple combination with tezacaftor and ivacaftor, improve CFTR processing, trafficking and function in vitro and have demonstrated clinical improvements in phase 2 studies in patients with CF with one or two F508del-CFTR alleles.Here, we present the rationale and design of four randomised phase 3 studies, and their open-label extensions, evaluating VX-659 (ECLIPSE) or VX-445 (AURORA) plus tezacaftor and ivacaftor in patients with one or two F508del-CFTR alleles.

Abstract P136: E2F2/4 Regulated by Serine 21 Phosphorylation of GSK-3α Play Compensatory Roles During Pressure Overload

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Takanobu Yamamoto ◽  
Yasuhiro Maejima ◽  
Peiyong Zhai ◽  
Takahisa Matsuda ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Glycogen Synthase ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Causative Role ◽  
Serine Threonine Kinase ◽  
Lv Dysfunction ◽  
Cardiac Phenotype ◽  
And Function

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with two isoforms, alpha and beta, which have distinct functions in cardiomyocytes (CMs). GSK-3alpha is phosphorylated at S21 during pressure overload (PO), and inhibition of S21 phosphorylation in GSK-3alpha S21A knock-in (alpha−KI) mice promotes hypertrophy and heart failure in response to PO, accompanied by decreases in the total number of CMs in the heart. Since GSK-3alpha downregulates cyclinD1 in the nucleus, GSK-3alpha may negatively regulate E2F-mediated transcription. Reporter gene assays showed that the transcriptional activity of E2F was increased by GSK-3alpha knockdown (1.75 fold, p<0.05). To evaluate the role of E2F isoforms in regulating cardiac hypertrophy and function during PO, E2F1−/−, E2F2−/+, E2F4−/+, and wild type (WT) mice were subjected to transverse aortic constriction (TAC). Left ventricular (LV) weight/ tibial length (LVW/TL) was significantly greater and LV ejection fraction (LVEF) was significantly decreased in both E2F2−/+ and E2F4−/+ after 2 weeks of TAC (LVW/TL: E2F2−/+=7.1±0.3, E2F4−/+=7.0±0.4, WT=5.9±0.3, p<0.05 vs. WT; LVEF: E2F2−/+=53±1%, E2F4−/+=61±2%, WT=75±1%, p<0.05 vs. WT). Thus, downregulation of either E2F2 or E2F4 induced a phenotype similar to that of alpha−KI in response to TAC. To examine the causative role of E2F2/E2F4 downregulation in mediating the cardiac phenotype in alpha-KI mice, adenovirus (Ad) harboring either E2F2 or E2F4 was injected into alpha-KI hearts. Rescue with E2F2 or E2F4 attenuated cardiac hypertrophy (LVW/TL: alpha−KI+E2F2=7.1±0.4, alpha−KI+E2F4=7.3±0.3, alpha−KI+LacZ=8.7±0.4, p<0.05 vs. alpha−KI+LacZ) and improved LV dysfunction (LVEF: alpha−KI+E2F2=66±3%, alpha−KI+E2F4=60±2%, alpha−KI+LacZ=39±2%, p<0.05 vs. alpha−KI+LacZ) in alpha−KI mice under PO conditions. Injection of either Ad-E2F2 or Ad-E2F4, but not of Ad-LacZ, significantly increased the number of Ki67-positive myocytes in the alpha-KI mice (alpha-KI+LacZ =0.7±0.3%, alpha-KI+E2F2=10.4±2.3%, alpha-KI+E2F4=9.2±1.5%, p<0.05 vs. alpha-KI+LacZ). These results suggest that maintaining the activity of E2F2 and E2F4 through S21 phosphorylation of GSK-3alpha plays an essential role in preserving cardiac function during PO.

scholarly journals PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer

Oncogene ◽  
2021 ◽  
Vol 40 (13) ◽  
pp. 2355-2366
Author(s):  
Laura C. A. Galbraith ◽  
Ernest Mui ◽  
Colin Nixon ◽  
Ann Hedley ◽  
David Strachan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mitochondrial Biogenesis ◽  
Nuclear Export ◽  
Epithelial To Mesenchymal Transition ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Serine Threonine Kinase ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mesenchymal Transition ◽  
And Function

AbstractPeroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.

scholarly journals Expression and function of Smad7 in autoimmune and inflammatory diseases

2021 ◽  
Author(s):  
Yiping Hu ◽  
Juan He ◽  
Lianhua He ◽  
Bihua Xu ◽  
Qingwen Wang
Keyword(s):  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Signaling Mechanism ◽  
And Function

AbstractTransforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

Liquid secretion inhibitors reduce mucociliary transport in glandular airways

2002 ◽  
Vol 283 (2) ◽  
pp. L329-L335 ◽  
Author(s):  
Stephen T. Ballard ◽  
Laura Trout ◽  
Anil Mehta ◽  
Sarah K. Inglis
Keyword(s):  
Beat Frequency ◽  
Anion Channel ◽  
Ciliary Beat Frequency ◽  
Mucociliary Transport ◽  
Transmembrane Conductance Regulator ◽  
Inhibitory Effects ◽  
Transmembrane Conductance ◽  
Regulator Protein ◽  
Liquid Absorption ◽  
Cf Transmembrane Conductance Regulator

Because of its possible importance in cystic fibrosis (CF) pulmonary pathogenesis, the effect of anion and liquid secretion inhibitors on airway mucociliary transport was examined. When excised porcine tracheas were treated with ACh to induce gland liquid secretion, the rate of mucociliary transport was increased nearly threefold from 2.5 ± 0.5 to 6.8 ± 0.8 mm/min. Pretreatment with both bumetanide and dimethylamiloride (DMA), to respectively inhibit Cl− and HCO[Formula: see text]secretion, significantly reduced mucociliary transport in the presence of ACh by 92%. Pretreatment with the anion channel blocker 5-nitro-2-(3-phenylpropylamino)benzoic acid similarly reduced mucociliary transport in ACh-treated airways by 97%. These agents did not, however, reduce ciliary beat frequency. Luminal application of benzamil to block liquid absorption significantly attenuated the inhibitory effects of bumetanide and DMA on mucociliary transport. We conclude that anion and liquid secretion is essential for normal mucociliary transport in glandular airways. Because the CF transmembrane conductance regulator protein likely mediates Cl−, HCO[Formula: see text], and liquid secretion in normal glands, we speculate that impairment of gland liquid secretion significantly contributes to defective mucociliary transport in CF.

scholarly journals Abnormal Cardiac Development in the Absence of Heart Glycogen

2004 ◽  
Vol 24 (16) ◽  
pp. 7179-7187 ◽  
Author(s):  
Bartholomew A. Pederson ◽  
Hanying Chen ◽  
Jill M. Schroeder ◽  
Weinian Shou ◽  
Anna A. DePaoli-Roach ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Muscle ◽  
Heart Development ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Glycogen Synthase ◽  
Heart Defects ◽  
Mendelian Inheritance ◽  
And Function ◽  
Impaired Cardiac Function

ABSTRACT Glycogen serves as a repository of glucose in many mammalian tissues. Mice lacking this glucose reserve in muscle, heart, and several other tissues were generated by disruption of the GYS1 gene, which encodes an isoform of glycogen synthase. Crossing mice heterozygous for the GYS1 disruption resulted in a significant underrepresentation of GYS1-null mice in the offspring. Timed matings established that Mendelian inheritance was followed for up to 18.5 days postcoitum (dpc) and that ∼90% of GYS1-null animals died soon after birth due to impaired cardiac function. Defects in cardiac development began between 11.5 and 14.5 dpc. At 18.5 dpc, the hearts were significantly smaller, with reduced ventricular chamber size and enlarged atria. Consistent with impaired cardiac function, edema, pooling of blood, and hemorrhagic liver were seen. Glycogen synthase and glycogen were undetectable in cardiac muscle and skeletal muscle from the surviving null mice, and the hearts showed normal morphology and function. Congenital heart disease is one of the most common birth defects in humans, at up to 1 in 50 live births. The results provide the first direct evidence that the ability to synthesize glycogen in cardiac muscle is critical for normal heart development and hence that its impairment could be a significant contributor to congenital heart defects.

scholarly journals Structure and function relationships of proteins based on polar profile: a review.

2016 ◽  
Vol 63 (2) ◽  
Author(s):  
Carlos Polanco ◽  
Thomas Buhse ◽  
Vladimir N Uversky
Keyword(s):  
Mathematical Structure ◽  
Quantitative Structure Activity Relationship ◽  
Multidrug Resistant ◽  
Training Data ◽  
Main Function ◽  
Pharmaceutical Drugs ◽  
Linear Sequence ◽  
Wide Range ◽  
High Level ◽  
And Function

Proteins in the post-genome era impose diverse research challenges, the main are the understanding of their structure-function mechanism, and the growing need for new pharmaceutical drugs, particularly antibiotics that help clinicians treat the ever- increasing number of Multidrug-Resistant Organisms (MDROs). Although, there is a wide range of mathematical-computational algorithms to satisfy the demand, among them the Quantitative Structure-Activity Relationship algorithms that have shown better performance using a characteristic training data of the property searched; their performance has stagnated regardless of the number of metrics they evaluate and their complexity. This article reviews the characteristics of these metrics, and the need to reconsider the mathematical structure that expresses them, directing their design to a more comprehensive algebraic structure. It also shows how the main function of a protein can be determined by measuring the polarity of its linear sequence, with a high level of accuracy, and how such exhaustive metric stands as a "fingerprint" that can be applied to scan the protein regions to obtain new pharmaceutical drugs, and thus to establish how the singularities led to the specialization of the protein groups known today.

scholarly journals The Impact of Cultural Diversity on Mosques in Malaysia

2018 ◽  
Vol 10 (2) ◽  
pp. 45
Author(s):  
Mansoureh Ebrahimi ◽  
Kamaruzaman Yusoff
Keyword(s):  
Cultural Diversity ◽  
Open Space ◽  
Main Function ◽  
Sacred Place ◽  
Islamic Perspective ◽  
And Function ◽  
The Impact ◽  
Country Planning

According to Malaysia Town and Country Planning Guideline and Standards (2002), two major considerations related to mosque usage and management are sufficient areas for both building and adjacent open space. As a sacred place for prostration to Almighty God, individually or in groups, mosque architecture has evolved considerably, from very simple designs and functions to more sophisticated forms and layouts. In Malaysia, various races have significantly influenced mosque design and function. The present work describes this evolution in terms of well-known mosques via qualitative observations and documentation, from earliest to latest architectural developments. Our findings demonstrate that architectural evolution and/or transformation did not alter the mosque’s main function from an Islamic perspective. Nonetheless, designs and structure did benefit usage, to include the attraction of tourists.

scholarly journals HOTAIR: An Oncogenic Long Non-Coding RNA in Human Cancer

2018 ◽  
Vol 47 (3) ◽  
pp. 893-913 ◽  
Author(s):  
Qing Tang ◽  
Swei Sunny Hann
Keyword(s):  
Drug Resistance ◽  
Human Cancer ◽  
Critical Role ◽  
Stem Cell Differentiation ◽  
Human Diseases ◽  
Biological Functions ◽  
Protein Coding ◽  
Non Coding Rna ◽  
And Function ◽  
Long Non Coding Rna

Long non-coding RNAs (LncRNAs) represent a novel class of noncoding RNAs that are longer than 200 nucleotides without protein-coding potential and function as novel master regulators in various human diseases, including cancer. Accumulating evidence shows that lncRNAs are dysregulated and implicated in various aspects of cellular homeostasis, such as proliferation, apoptosis, mobility, invasion, metastasis, chromatin remodeling, gene transcription, and post-transcriptional processing. However, the mechanisms by which lncRNAs regulate various biological functions in human diseases have yet to be determined. HOX antisense intergenic RNA (HOTAIR) is a recently discovered lncRNA and plays a critical role in various areas of cancer, such as proliferation, survival, migration, drug resistance, and genomic stability. In this review, we briefly introduce the concept, identification, and biological functions of HOTAIR. We then describe the involvement of HOTAIR that has been associated with tumorigenesis, growth, invasion, cancer stem cell differentiation, metastasis, and drug resistance in cancer. We also discuss emerging insights into the role of HOTAIR as potential biomarkers and therapeutic targets for novel treatment paradigms in cancer.

Abstract 42: Differential Contribution Of The N- And C-terminal Domains To The Folding And Function Of Tandem Calponin-homology Domains

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Krishna Mallela ◽  
Swati Bandi ◽  
Surinder Singh ◽  
Geoffrey Armstrong
Keyword(s):  
Full Length ◽  
Actin Binding ◽  
Main Function ◽  
Calponin Homology ◽  
Terminal Domain ◽  
Binding Domains ◽  
Binding Function ◽  
Ch2 Domain ◽  
The Stability ◽  
And Function

Tandem calponin-homology (CH) domains constitute a major class of actin-binding domains that include dystrophin and utrophin, the two key proteins involved in muscular dystrophy. Despite their importance, how their structure controls their function is not understood. Here, we study the contribution of individual CH domains to the actin-binding function and thermodynamic stability of utrophin’s tandem CH domain. Traditional actin co-sedimentation assays indicate that the isolated C-terminal CH2 domain binds weakly to F-actin when compared with the full-length tandem CH domain. In contrast, isolated CH1 binds to F-actin with a similar efficiency as that of the full-length tandem CH domain. Thus, the obvious question that arises is why tandem CH domains require CH2, when their actin-binding efficiency is originating primarily from CH1. To answer, we probed the thermodynamic stabilities of individual CH domains. Isolated CH1 domain is unstable and is prone to serious aggregation. Isolated CH2 is very stable, even appears to be more stable than the full-length tandem CH domain. In addition, the CH2 domain, which is more stable, is less functional. These results indicate that the main function of CH2 is to stabilize CH1. Consistently, the proposed structure of utrophin’s tandem CH domain based on earlier X-ray studies indicates a close proximity between the C-terminal helix of CH2 and the N-terminal helix of CH1, and this helix in CH2 is more dynamic in the full-length protein when compared with that in the absence of CH1, suggesting the mechanism by which CH2 stabilizes CH1. These observations indicate that the two CH domains contribute differentially to the folding and function of tandem CH domains, although both domains essentially have the same native structure in the tandem CH domain. The N-terminal domain determines the function, whereas the C-terminal domain determines the stability. This work was funded by the AHA Grant 11SDG4880046.

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