scholarly journals The Ets protein Pointed P1 represses Asense expression in type II neuroblasts by activating Tailless

2021 ◽  
Author(s):  
Rui Chen ◽  
Xiaobing Deng ◽  
Sijun Zhu
Keyword(s):  
Binding Sites ◽  
Molecular Mechanisms ◽  
Neural Progenitors ◽  
Type Ii ◽  
Molecular Approaches ◽  
Downstream Effector ◽  
Dna Elements ◽  
Direct Target ◽  
Ets Transcription Factor ◽  
Half Site

Intermediate neural progenitors (INPs) boost the number and diversity of neurons generated from neural stem cells (NSCs) by undergoing transient proliferation. In the developing Drosophila brains, INPs are generated from type II neuroblasts (NBs). In order to maintain type II NB identity and their capability to produce INPs, the proneural protein Asense (Ase) needs to be silenced by the Ets transcription factor pointed P1 (PntP1), a master regulator of type II NB development. However, the molecular mechanisms underlying the PntP1-mediated suppression of Ase is still unclear. In this study, we utilized genetic and molecular approaches to determine the transcriptional property of PntP1 and identify the direct downstream effector of PntP1 and the cis- DNA elements that mediate the suppression of ase. Our results demonstrate that PntP1 directly activates the expression of the transcriptional repressor, Tailless (Tll), by binding to seven Ets-binding sites, and Tll in turn suppresses the expression of Ase in type II NBs by binding to two hexameric core half-site motifs. We further show that Tll provides positive feedback to maintain the expression of PntP1 and the identity of type II NBs. Thus, our study identifies a novel direct target of PntP1 and reveals mechanistic details of the specification and maintenance of the type II NB identity by PntP1.

scholarly journals Eosinophils as the source of uterine nuclear type II estrogen binding sites.

1984 ◽  
Vol 259 (5) ◽  
pp. 2697-2700
Author(s):  
C R Lyttle ◽  
K L Medlock ◽  
D M Sheehan
Keyword(s):  
Binding Sites ◽  
Type Ii ◽  
Estrogen Binding

scholarly journals Crystal structures of aconitase X enzymes from bacteria and archaea provide insights into the molecular evolution of the aconitase superfamily

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Seiya Watanabe ◽  
Yohsuke Murase ◽  
Yasunori Watanabe ◽  
Yasuhiro Sakurai ◽  
Kunihiko Tajima
Keyword(s):  
Molecular Evolution ◽  
Agrobacterium Tumefaciens ◽  
Crystal Structures ◽  
Epr Spectroscopy ◽  
Binding Sites ◽  
Active Sites ◽  
Type I ◽  
Type Ii ◽  
Thermococcus Kodakarensis ◽  
Evolutionary Scenario

AbstractAconitase superfamily members catalyze the homologous isomerization of specific substrates by sequential dehydration and hydration and contain a [4Fe-4S] cluster. However, monomeric and heterodimeric types of function unknown aconitase X (AcnX) have recently been characterized as a cis-3-hydroxy-L-proline dehydratase (AcnXType-I) and mevalonate 5-phosphate dehydratase (AcnXType-II), respectively. We herein elucidated the crystal structures of AcnXType-I from Agrobacterium tumefaciens (AtAcnX) and AcnXType-II from Thermococcus kodakarensis (TkAcnX) without a ligand and in complex with substrates. AtAcnX and TkAcnX contained the [2Fe-2S] and [3Fe-4S] clusters, respectively, conforming to UV and EPR spectroscopy analyses. The binding sites of the [Fe-S] cluster and substrate were clearlydifferent from those that were completely conserved in other aconitase enzymes; however, theoverall structural frameworks and locations of active sites were partially similar to each other.These results provide novel insights into the evolutionary scenario of the aconitase superfamilybased on the recruitment hypothesis.

scholarly journals Expression of Phosphocitrate-Targeted Genes in Osteoarthritis Menisci

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Yubo Sun ◽  
David R. Mauerhan ◽  
Nury M. Steuerwald ◽  
Jane Ingram ◽  
Jeffrey S. Kneisl ◽  
...  
Keyword(s):  
Immune System ◽  
Molecular Mechanisms ◽  
Fibroblast Growth Factor Receptor ◽  
Collagen Type ◽  
Skeletal Development ◽  
Growth Factor Receptor ◽  
Type Ii ◽  
Immune System Activation ◽  
System Activation ◽  
Disease Modifying

Phosphocitrate (PC) inhibited calcium crystal-associated osteoarthritis (OA) in Hartley guinea pigs. However, the molecular mechanisms remain elusive. This study sought to determine PC targeted genes and the expression of select PC targeted genes in OA menisci to test hypothesis that PC exerts its disease modifying activity in part by reversing abnormal expressions of genes involved in OA. We found that PC downregulated the expression of numerous genes classified in immune response, inflammatory response, and angiogenesis, including chemokine (C-C motif) ligand 5, Fc fragment of IgG, low affinity IIIb receptor (FCGR3B), and leukocyte immunoglobulin-like receptor, subfamily B member 3 (LILRB3). In contrast, PC upregulated the expression of many genes classified in skeletal development, including collagen type II alpha1, fibroblast growth factor receptor 3 (FGFR3), and SRY- (sex determining region Y-) box 9 (SOX-9). Immunohistochemical examinations revealed higher levels of FCGR3B and LILRB3 and lower level of SOX-9 in OA menisci. These findings indicate that OA is a disease associated with immune system activation and decreased expression of SOX-9 gene in OA menisci. PC exerts its disease modifying activity on OA, at least in part, by targeting immune system activation and the production of extracellular matrix and selecting chondroprotective proteins.

Type II oestrogen binding sites in acute lymphoid and myeloid leukaemias: growth inhibitory effect of oestrogen and flavonoids

1990 ◽  
Vol 75 (4) ◽  
pp. 489-495 ◽  
Author(s):  
L. M. Larocca ◽  
M. Piantelli ◽  
G. Leone ◽  
S. Sica ◽  
L. Teofili ◽  
...  
Keyword(s):  
Binding Sites ◽  
Inhibitory Effect ◽  
Type Ii ◽  
Growth Inhibitory Effect ◽  
Growth Inhibitory

scholarly journals Type II transmembrane serine proteases as potential targets for cancer therapy

2016 ◽  
Vol 397 (9) ◽  
pp. 815-826 ◽  
Author(s):  
Andrew S. Murray ◽  
Fausto A. Varela ◽  
Karin List
Keyword(s):  
Cancer Progression ◽  
Serine Proteases ◽  
Molecular Mechanisms ◽  
Inflammatory Cells ◽  
Activity Levels ◽  
Type Ii ◽  
Neoplastic Progression ◽  
Treatment Regimens ◽  
Proinflammatory Mediators ◽  
Transmembrane Serine Protease

Abstract Carcinogenesis is accompanied by increased protein and activity levels of extracellular cell-surface proteases that are capable of modifying the tumor microenvironment by directly cleaving the extracellular matrix, as well as activating growth factors and proinflammatory mediators involved in proliferation and invasion of cancer cells, and recruitment of inflammatory cells. These complex processes ultimately potentiate neoplastic progression leading to local tumor cell invasion, entry into the vasculature, and metastasis to distal sites. Several members of the type II transmembrane serine protease (TTSP) family have been shown to play critical roles in cancer progression. In this review the knowledge collected over the past two decades about the molecular mechanisms underlying the pro-cancerous properties of selected TTSPs will be summarized. Furthermore, we will discuss how these insights may facilitate the translation into clinical settings in the future by specifically targeting TTSPs as part of novel cancer treatment regimens.

ERP, a new member of the ets transcription factor/oncoprotein family: cloning, characterization, and differential expression during B-lymphocyte development

1994 ◽  
Vol 14 (5) ◽  
pp. 3292-3309
Author(s):  
M Lopez ◽  
P Oettgen ◽  
Y Akbarali ◽  
U Dendorfer ◽  
T A Libermann
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Gene Family ◽  
B Cell ◽  
Binding Sites ◽  
B Lymphocyte ◽  
Striking Similarity ◽  
Lymphocyte Development ◽  
B Lymphocyte Development ◽  
Ets Transcription Factor

The ets gene family encodes a group of proteins which function as transcription factors under physiological conditions and, if aberrantly expressed, can cause cellular transformation. We have recently identified two regulatory elements in the murine immunoglobulin heavy-chain (IgH) enhancer, pi and microB, which exhibit striking similarity to binding sites for ets-related proteins. To identify ets-related transcriptional regulators expressed in pre-B lymphocytes that may interact with either the pi or the microB site, we have used a PCR approach with degenerate oligonucleotides encoding conserved sequences in all members of the ets family. We have cloned the gene for a new ets-related transcription factor, ERP (ets-related protein), from the murine pre-B cell line BASC 6C2 and from mouse lung tissue. The ERP protein contains a region of high homology with the ETS DNA-binding domain common to all members of the ets transcription factor/oncoprotein family. Three additional smaller regions show homology to the ELK-1 and SAP-1 genes, a subgroup of the ets gene family that interacts with the serum response factor. Full-length ERP expresses only negligible DNA-binding activity by itself. Removal of the carboxy terminus enables ERP to interact with a variety of ets-binding sites including the E74 site, the IgH enhancer pi site, and the lck promoter ets site, suggesting a carboxy-terminal negative regulatory domain. At least three ERP-related transcripts are expressed in a variety of tissues. However, within the B-cell lineage, ERP is highly expressed primarily at early stages of B-lymphocyte development, and expression declines drastically upon B-cell maturation, correlating with the enhancer activity of the IgH pi site. These data suggest that ERP might play a role in B-cell development and in IgH gene regulation.

scholarly journals Dust from hog confinement facilities impairs Ca2+ mobilization from sarco(endo)plasmic reticulum by inhibiting ryanodine receptors

2013 ◽  
Vol 114 (5) ◽  
pp. 665-674
Author(s):  
Chengju Tian ◽  
Caronda J. Moore ◽  
Puttappa Dodmane ◽  
Chun Hong Shao ◽  
Debra J. Romberger ◽  
...  
Keyword(s):  
Binding Sites ◽  
Molecular Mechanisms ◽  
Ryanodine Receptors ◽  
Cell Types ◽  
C2c12 Cells ◽  
Common Element ◽  
Plasmic Reticulum ◽  
Skeletal Muscle Weakness ◽  
Intracellular Ca ◽  
Phosphate Buffered Saline

Individuals working in commercial hog confinement facilities have elevated incidences of headaches, depression, nausea, skeletal muscle weakness, fatigue, gastrointestinal disorders, and cardiovascular diseases, and the molecular mechanisms for these nonrespiratory ailments remain incompletely undefined. A common element underlying these diverse pathophysiologies is perturbation of intracellular Ca2+ homeostasis. This study assessed whether the dust generated inside hog confinement facilities contains compounds that alter Ca2+ mobilization via ryanodine receptors (RyRs), key intracellular channels responsible for mobilizing Ca2+ from internal stores to elicit an array of physiologic functions. Hog barn dust (HBD) was extracted with phosphate-buffered saline, sterile-filtered (0.22 μm), and size-separated using Sephadex G-100 resin. Fractions (F) 1 through 9 (Mw >10,000 Da) had no measurable effects on RyR isoforms. However, F10 through F17, which contained compounds of Mw ≤2,000 Da, modulated the [3H]ryanodine binding to RyR1, RyR2, and RyR3 in a biphasic (Gaussian) manner. The Ki values for F13, the most potent fraction, were 3.8 ± 0.2 μg/ml for RyR1, 0.2 ± 0.01 μg/ml and 19.1 ± 2.8 μg/ml for RyR2 (two binding sites), and 44.9 ± 2.8 μg/ml and 501.6 ± 9.2 μg/ml for RyR3 (two binding sites). In lipid bilayer assays, F13 dose-dependently decreased the open probabilities of RyR1, RyR2, and RyR3. Pretreating differentiated mouse skeletal myotubes (C2C12 cells) with F13 blunted the amplitudes of ryanodine- and K+-induced Ca2+ transients. Because RyRs are present in many cell types, impairment in Ca2+ mobilization from internal stores via these channels is a possible mechanism by which HBD may trigger these seemingly unrelated pathophysiologies.

scholarly journals Эколого-биологическая характеристика Lactobacillus acidophilus

2017 ◽  
Vol 7 (4) ◽  
pp. 214-230 ◽  
Author(s):  
A. N. Irkitova ◽  
A. V. Matsyura
Keyword(s):  
Lactobacillus Acidophilus ◽  
Pathogenic Bacteria ◽  
Molecular Mechanisms ◽  
Systematic Position ◽  
New Class ◽  
Safe Level ◽  
Molecular Approaches ◽  
The Family ◽  
Long Time ◽  
Biochemical Identification

<p>Lactobacillus acidophilus - homofermentative lactobacillus, specializing in living in the gastrointestinal and urogenital tracts of mammals and birds. It accompanies a person from birth and throughout his life, providing a whole range of useful services, the main one of which is active participation in the body's defense system against the harmful action of undesirable microorganisms (preventing the growth of pathogenic bacteria and restraining populations of opportunistic microbes at a safe level) . It is this property of the acidophilus rod that explains its wide practical use in various probiotic products and preparations of dietary, medical and agricultural purposes.<br />Although the acidophilus rod is known and purposefully used for a long time, it still ha the great potential for the research. The use of gene-molecular approaches has made it possible to clarify the systematic position of L. acidophilus in the family of lactobacilli and to identify a group of closely related species, often indistinguishable by traditional physiological and biochemical identification methods. Today, the efforts of researchers are focused on elucidating the molecular mechanisms by which antagonistically active strains of L. acidophilus carry out a bactericidal and bacteriolytic effect on harmful microbes. Disclosure of these mechanisms will not only allow more efficient selection and use of strains of L. acidophilus, but also create a new class of antibiotics that are more effective and have less side effects than existing ones.<br />This review is devoted to the description of the probiotic microorganism Lactobacillus acidophilus. In the article the biological and ecological properties of the acidophilus rod are described in detail, examples of practical use of this microorganism in various branches of the national economy are given.</p>

scholarly journals Elucidating Binding Sites and Affinities of ERα Agonist and Antagonist to Human Alpha-Fetoprotein by in silico Modeling and Point Mutagenesis

2019 ◽  
Author(s):  
Nurbubu T. Moldogazieva ◽  
Daria S. Ostroverkhova ◽  
Nikolai N. Kuzmich ◽  
Vladimir V. Kadochnikov ◽  
Alexander A. Terentiev ◽  
...  
Keyword(s):  
Binding Sites ◽  
In Silico ◽  
Disulfide Bonds ◽  
Electrostatic Interactions ◽  
Molecular Mechanisms ◽  
3D Structure ◽  
Scoring Function ◽  
Alpha Fetoprotein ◽  
Ligand Interaction ◽  
Ligand Interactions

Alpha-fetoprotein (AFP) is a major embryo- and tumor-associated protein capable of binding and transporting variety of hydrophobic ligands including estrogens. AFP has been shown to inhibit estrogen receptor (ER)-positive tumor growth and this can be attributed to its estrogen-binding ability. Despite AFP has long been investigated, its three-dimensional (3D) structure has not been experimentally resolved and molecular mechanisms underlying AFP-ligand interaction remain obscure. In our study we constructed homology-based 3D model of human AFP (HAFP) with the purpose to perform docking of ER&alpha; ligands, three agonists (17&beta;-estradiol, estrone and diethylstilbestrol) and three antagonists (tamoxifen, afimoxifene and endoxifen) into the obtained structure. Based on ligand docked scoring function, we identified three putative estrogen- and antiestrogen-binding sites with different ligand binding affinities. Two high-affinity sites were located in (i) a tunnel formed within HAFP subdomains IB and IIA and (ii) opposite side of the molecule in a groove originating from cavity formed between domains I and III, while (iii) the third low-affinity site was found at the bottom of the cavity. 100 ns MD simulation allowed studying their geometries and showed that HAFP-estrogen interactions occur due to van der Waals forces, while both hydrophobic and electrostatic interactions were almost equally involved in HAFP-antiestrogen binding. MM/GBSA rescoring method estimated binding free energies (&Delta;Gbind) and showed that antiestrogens have higher affinities to HAFP as compared to estrogens. We performed in silico point substitutions of amino acid residues to confirm their roles in HAFP-ligand interactions and showed that Thr132, Leu138, His170, Phe172, Ser217, Gln221, His266, His316, Lys453, and Asp478 residues along two disulfide bonds, Cys224-Cys270 and Cys269-Cys277 have key roles in both HAFP-estrogen and HAFP-antiestrogen binding. Data obtained in our study contribute to understanding mechanisms underlying protein-ligand interactions and anti-cancer therapy strategies based on ER-binding ligands.

scholarly journals Hermansky-Pudlak Syndrome and Lung Disease: Pathogenesis and Therapeutics

2021 ◽  
Vol 12 ◽  
Author(s):  
Pamela Velázquez-Díaz ◽  
Erika Nakajima ◽  
Parand Sorkhdini ◽  
Ashley Hernandez-Gutierrez ◽  
Adam Eberle ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Molecular Mechanisms ◽  
Management Strategies ◽  
Oculocutaneous Albinism ◽  
Alveolar Epithelial Cells ◽  
Multisystem Disorder ◽  
Alveolar Epithelial ◽  
Novel Treatments ◽  
Molecular Approaches ◽  
Hermansky Pudlak Syndrome

Hermansky-Pudlak Syndrome (HPS) is a rare, genetic, multisystem disorder characterized by oculocutaneous albinism (OCA), bleeding diathesis, immunodeficiency, granulomatous colitis, and pulmonary fibrosis. HPS pulmonary fibrosis (HPS-PF) occurs in 100% of patients with subtype HPS-1 and has a similar presentation to idiopathic pulmonary fibrosis. Upon onset, individuals with HPS-PF have approximately 3 years before experiencing signs of respiratory failure and eventual death. This review aims to summarize current research on HPS along with its associated pulmonary fibrosis and its implications for the development of novel treatments. We will discuss the genetic basis of the disease, its epidemiology, and current therapeutic and clinical management strategies. We continue to review the cellular processes leading to the development of HPS-PF in alveolar epithelial cells, lymphocytes, mast cells, and fibrocytes, along with the molecular mechanisms that contribute to its pathogenesis and may be targeted in the treatment of HPS-PF. Finally, we will discuss emerging new cellular and molecular approaches for studying HPS, including lentiviral-mediated gene transfer, induced pluripotent stem cells (iPSCs), organoid and 3D-modelling, and CRISPR/Cas9-based gene editing approaches.

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