scholarly journals Structure-based Discovery of a Series of NSD2-PWWP1 Inhibitors

2021 ◽  
Author(s):  
Na Li ◽  
Hong Yang ◽  
Ke Liu ◽  
Liwei Zhou ◽  
Yuting Huang ◽  
...  
Keyword(s):  
Drug Target ◽  
High Selectivity ◽  
Catalytic Domain ◽  
Point Mutations ◽  
Biological Evaluation ◽  
Future Research ◽  
Expression Of Genes ◽  
Lysine Methyltransferase ◽  
Specific Regulation ◽  
Regulation Mode

Overexpression, point mutations or translocations of protein lysine methyltransferase NSD2 was occurred in many types of cancer cells. Therefore, it was recognized as onco-protein and considered as a promising anticancer drug target. NSD2 consists of a SET catalytic domain and two PWWP domains binding to methylated histone proteins. Here, we reported our efforts to develop a series of NSD2-PWWP1 inhibitors, and further structure-based optimization resulted a potent inhibitor 38, which has the high selectivity towards NSD2-PWWP1 domain. The detailed biological evaluation revealed that compound 38 can bind to NSD2-PWWP1 and then affect the expression of genes regulated by NSD2. The current discovery will provide a useful chemical probe to the future research in understanding the specific regulation mode of NSD2 by PWWP1 recognition, and pave the way to develop potential drugs targeting NSD2 protein.

scholarly journals Structure-based Discovery of a Series of NSD2-PWWP1 Inhibitor

2021 ◽  
Author(s):  
Liwei Zhou ◽  
Hong Yang ◽  
Ke Liu ◽  
Yuting Huang ◽  
Danyan Cao ◽  
...  
Keyword(s):  
Drug Target ◽  
High Selectivity ◽  
Catalytic Domain ◽  
Point Mutations ◽  
Biological Evaluation ◽  
Future Research ◽  
Expression Of Genes ◽  
Lysine Methyltransferase ◽  
Specific Regulation ◽  
Regulation Mode

Overexpression, point mutations or translocations of protein lysine methyltransferase NSD2 was occurred in many types of cancer cells. Therefore, it was recognized as onco-protein and considered as a promising anticancer drug target. NSD2 consists of a SET catalytic domain and two PWWP domains binding to methylated histone proteins. Here, we reported our efforts to develop a series of NSD2 PWWP1 inhibitors, and further structure-based optimization resulted a potent inhibitor 38, which has the high selectivity towards NSD2 PWWP1 domain. The detailed biological evaluation revealed that compound 38 can bind to NSD2-PWWP1 and then affect the expression of genes regulated by NSD2. We believe that the current discovery will provide a useful chemical probe to the future research in understanding the specific regulation mode of NSD2 by PWWP1 recognition.

Effects of lipotoxicity on a novel insulin-secreting human pancreatic β-cell line, 1.1B4

2013 ◽  
Vol 394 (7) ◽  
pp. 909-918 ◽  
Author(s):  
Srividya Vasu ◽  
Neville H. McClenaghan ◽  
Jane T. McCluskey ◽  
Peter R. Flatt
Keyword(s):  
Mrna Expression ◽  
Cell Line ◽  
Molecular Mechanisms ◽  
Endoplasmic Reticulum Stress Response ◽  
Future Research ◽  
The Novel ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Expression Of Genes ◽  
Cellular Ca

Abstract The novel insulin-secreting human pancreatic β-cell line, 1.1B4, demonstrates stability in culture and many of the secretory functional attributes of human pancreatic β-cells. This study investigated the cellular responses of 1.1B4 cells to lipotoxicity. Chronic 18-h exposure of 1.1B4 cells to 0.5 mm palmitate resulted in decreased cell viability and insulin content. Secretory responses to classical insulinotropic agents and cellular Ca2+ handling were also impaired. Palmitate decreased glucokinase activity and mRNA expression of genes involved in secretory function but up-regulated mRNA expression of HSPA5, EIF2A, and EIF2AK3, implicating activation of the endoplasmic reticulum stress response. Palmitate also induced DNA damage and apoptosis of 1.1B4 cells. These responses were accompanied by increased gene expression of the antioxidant enzymes SOD1, SOD2, CAT and GPX1. This study details molecular mechanisms underlying lipotoxicity in 1.1B4 cells and indicates the potential value of the novel β-cell line for future research.

scholarly journals Expression of genes SBP and leginsulin in contrasting soybean seed coats

2016 ◽  
Vol 46 (10) ◽  
pp. 1695-1700
Author(s):  
Carlos André Bahry ◽  
Paulo Dejalma Zimmer
Keyword(s):  
Gene Expression ◽  
Seed Quality ◽  
Soybean Seed ◽  
Future Research ◽  
Expression Of Genes ◽  
New Information ◽  
Soybean Genotypes ◽  
Phases Of Development ◽  
Seed Coats ◽  
Early Phases

ABSTRACT: Evaluation of differential candidate gene expression in contrasting soybean seeds is an auxiliary tool in the partial elucidation of processes involved in seeds formation, as well as it contributes to the generation of new information that can be used in future research or in the development of r genetic superior constitutions. The aim of this study was to evaluate the expression of two candidate genes, SBP and leginsulin genes, possibly involved in seed quality, in contrasting coats of four soybean genotypes. Two cultivars of yellow soybeans were used, BMX Potência RR and CD 202, and two lines of black soybean, TP and IAC. Gene expression was evaluated using qPCR in seven stages of development from seed coats for four genotypes, at 25, 30, 35, 40, 45, 50, and 55 days after anthesis. The design was completely randomized, with three replications. Data were subjected to analysis of variance and means compared by Tukey's test at 5% probability. SBP and leginsulin gene have higher expression in the early phases of development from seed coats of BMX Potência RR cultivar, followed by the IAC line. These genotypes are therefore of interest for further research involving these genes.

scholarly journals Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance

2017 ◽  
Author(s):  
Stephen J. Pettitt ◽  
Dragomir B. Krastev ◽  
Inger Brandsma ◽  
Amy Drean ◽  
Feifei Song ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Point Mutations ◽  
Underlying Mechanism ◽  
Parp Inhibitors ◽  
High Density ◽  
Single Amino Acid ◽  
Genome Wide ◽  
Amino Acid Mutations

AbstractPARP inhibitors (PARPi) target homologous recombination defective tumour cells via synthetic lethality. Genome-wide and high-density CRISPR-Cas9 “tag, mutate and enrich” mutagenesis screens identified single amino acid mutations in PARP1 that cause profound PARPi-resistance. These included PARP1 mutations outside of the DNA interacting regions of the protein, such as mutations in solvent exposed regions of the catalytic domain and clusters of mutations around points of contact between ZnF, WGR and HD domains. These mutations altered PARP1 trapping, as did a mutation found in a clinical case of PARPi resistance. These genetic studies reinforce the importance of trapped PARP1 as a key cytotoxic DNA lesion and suggest that interactions between non-DNA binding domains of PARP1 influence cytotoxicity. Finally, different mechanisms of PARPi resistance (BRCA1 reversion, PARP1, 53BP1, REV7 mutation) had differing effects on chemotherapy sensitivity, suggesting that the underlying mechanism of PARPi resistance likely influences the success of subsequent therapies.

scholarly journals Identification of key genes and associated pathways in neuroendocrine tumors through bioinformatics analysis and predictions of small drug molecules

2020 ◽  
Author(s):  
Praveenkumar Devarbhavi ◽  
Basavaraj Vastrad ◽  
Anandkumar Tengli ◽  
Chanabasayya Vastrad ◽  
Iranna Kotturshetti
Keyword(s):  
Drug Target ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Regulatory Elements ◽  
Future Research ◽  
High Morbidity ◽  
Hub Genes ◽  
Go Enrichment ◽  
Significant Difference

AbstractNeuroendocrine tumor (NET) is one of malignant cancer and is identified with high morbidity and mortality rates around the world. With indigent clinical outcomes, potential biomarkers for diagnosis, prognosis and drug target are crucial to explore. The aim of this study is to examine the gene expression module of NET and to identify potential diagnostic and prognostic biomarkers as well as to find out new drug target. The differentially expressed genes (DEGs) identified from GSE65286 dataset was used for pathway enrichment analyses and gene ontology (GO) enrichment analyses and protein - protein interaction (PPI) analysis and module analysis. Moreover, miRNAs and transcription factors (TFs) that regulated the up and down regulated genes were predicted. Furthermore, validation of hub genes was performed. Finally, molecular docking studies were performed. DEGs were identified, including 453 down regulated and 459 up regulated genes. Pathway and GO enrichment analysis revealed that DEGs were enriched in sucrose degradation, creatine biosynthesis, anion transport and modulation of chemical synaptic transmission. Important hub genes and target genes were identified through PPI network, modules, target gene - miRNA network and target gene - TF network. Finally, survival analyses, receiver operating characteristic (ROC) curve and RT-PCR validated the significant difference of ATP1A1, LGALS3, LDHA, SYK, VDR, OBSL1, KRT40, WWOX, NINL and PPP2R2B between metastatic NET and normal controls. In conclusion, the DEGs and hub genes with their regulatory elements identified in this study will help us understand the molecular mechanisms underlying NET and provide candidate targets for future research.

scholarly journals Biological Evaluation, Molecular Docking, and SAR Studies of Novel 2-(2,4-Dihydroxyphenyl)-1H- Benzimidazole Analogues

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 870
Author(s):  
Joanna Matysiak ◽  
Alicja Skrzypek ◽  
Monika Karpińska ◽  
Kamila Czarnecka ◽  
Paweł Szymański ◽  
...  
Keyword(s):  
Molecular Docking ◽  
High Selectivity ◽  
Antioxidant Properties ◽  
Binding Mode ◽  
Biological Evaluation ◽  
The Other ◽  
Docking Simulations ◽  
Sar Studies ◽  
Structure Activity

In the present study, new 4-(1H-benzimidazol-2-yl)-benzene-1,3-diols, modified in both rings, have been synthesized and their efficacies as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors have been determined. The modified Ellman’s spectrophotometric method was applied for the biological evaluation. The compounds showed strong (IC50 80–90 nM) AChE and moderate (IC50 5–0.2 µM) BuChE inhibition in vitro. Some compounds were effective toward AChE/BuChE, exhibiting high selectivity ratios versus BuChE, while the other compounds were active against both enzymes. The structure–activity relationships were discussed. The compounds inhibited also in vitro self-induced Aβ(1–42) aggregation and exhibited antioxidant properties. The docking simulations showed that the benzimidazoles under consideration interact mainly with the catalytic site of AChE and mimic the binding mode of tacrine.

Molecular Mechanisms of FVII Deficiency: Expression of Mutations Clustered in the IVS7 Donor Splice Site of Factor VII Gene

Blood ◽  
1998 ◽  
Vol 92 (5) ◽  
pp. 1646-1651 ◽  
Author(s):  
M. Pinotti ◽  
R. Toso ◽  
R. Redaelli ◽  
M. Berrettini ◽  
G. Marchetti ◽  
...  
Keyword(s):  
Splice Site ◽  
Molecular Mechanisms ◽  
Catalytic Domain ◽  
Point Mutations ◽  
Factor Vii ◽  
Donor Splice Site ◽  
Donor Splice ◽  
Expression Studies ◽  
Fvii Deficiency ◽  
American Society

Abstract In three Italian patients, two point mutations and a short deletion were found in the intron 7 of factor VII gene, clustered in the donor splice site and located in the first of several repeats. The mutation 9726+5G→A, the most frequent cause of symptomatic factor VII deficiency in Italy, as well as the deletion (9729del4) gave rise in expression studies to abnormally spliced transcripts, which were exclusively produced from the cryptic site in the second repeat. The insertion in the mature mRNA of the first intronic repeat caused (9726+5G→A) a reading frameshift, abolishing most of the factor VII catalytic domain, or produced (9729del4), an altered factor with 11 additional residues, the activity of which was not detectable in the cell medium after mutagenesis and expression studies. Studies of factor VII ectopic mRNA from leukocytes and expression studies indicated that the deleted gene produced 30% of normally spliced transcript. Differently, the 9726+5G→A mutation permitted a very low level (0.2% to 1%) of correct splicing to occur, which could be of great importance to prevent the onset, in the homozygous patients, of most of the life-threatening bleeding symptoms. The 9726+7A→G mutation was found to be a rare and functionally silent polymorphism. These findings, which provide further evidence of the interplay of sequence and position in the 5′ splice site selection, throw light on the heterogeneous molecular bases and clinical phenotypes of FVII deficiency. © 1998 by The American Society of Hematology.

scholarly journals PGC-1α alternative promoter (Exon 1b) controls augmentation of total PGC-1α gene expression in response to cold water immersion and low glycogen availability

2020 ◽  
Vol 120 (11) ◽  
pp. 2487-2493
Author(s):  
R. Allan ◽  
J. P. Morton ◽  
G. L. Close ◽  
B. Drust ◽  
W. Gregson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cold Water ◽  
Water Immersion ◽  
Cold Water Immersion ◽  
Alternative Promoter ◽  
Future Research ◽  
Peroxisome Proliferator ◽  
Local Cooling ◽  
Post Exercise ◽  
Specific Regulation

AbstractThis investigation sought to determine whether post-exercise cold water immersion and low glycogen availability, separately and in combination, would preferentially activate either the Exon 1a or Exon 1b Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) promoter. Through a reanalysis of sample design, we identified that the systemic cold-induced augmentation of total PGC-1α gene expression observed previously (Allan et al. in J Appl Physiol 123(2):451–459, 2017) was largely a result of increased expression from the alternative promoter (Exon 1b), rather than canonical promoter (Exon 1a). Low glycogen availability in combination with local cooling of the muscle (Allan et al. in Physiol Rep 7(11):e14082, 2019) demonstrated that PGC-1α alternative promoter (Exon 1b) expression continued to rise at 3 h post-exercise in all conditions; whilst, expression from the canonical promoter (Exon 1a) decreased between the same time points (post-exercise–3 h post-exercise). Importantly, this increase in PGC-1α Exon 1b expression was reduced compared to the response of low glycogen or cold water immersion alone, suggesting that the combination of prior low glycogen and CWI post-exercise impaired the response in gene expression versus these conditions individually. Data herein emphasise the influence of post-exercise cooling and low glycogen availability on Exon-specific control of total PGC-1 α gene expression and highlight the need for future research to assess Exon-specific regulation of PGC-1α.

scholarly journals Distinct Patterns of Gene Expression Associated with Development of Fluconazole Resistance in Serial Candida albicansIsolates from Human Immunodeficiency Virus-Infected Patients with Oropharyngeal Candidiasis

1998 ◽  
Vol 42 (11) ◽  
pp. 2932-2937 ◽  
Author(s):  
Jose L. Lopez-Ribot ◽  
Robert K. McAtee ◽  
Linda N. Lee ◽  
William R. Kirkpatrick ◽  
Theodore C. White ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Immunodeficiency Virus ◽  
Sequence Data ◽  
Point Mutations ◽  
Oropharyngeal Candidiasis ◽  
Fluconazole Resistance ◽  
Expression Of Genes ◽  
Immunodeficiency Virus ◽  
Major Facilitator ◽  
Abc Transporter Genes

ABSTRACT Resistance to fluconazole is becoming an increasing problem in the management of oropharyngeal candidiasis in human immunodeficiency virus-infected patients. Strains obtained from five patients developed decreased fluconazole susceptibility over time. DNA strain typing confirmed the high degree of relatedness among isolates from one patient and the variability among isolates from different patients. Expression of genes involved in development of fluconazole resistance was monitored in each isolate using probes specific for ERG11 (lanosterol 14α-demethylase), MDR1 (a major facilitator), andCDR (ATP-binding cassette or ABC transporter) genes. Increased expression of CDR genes was detected in the series of isolates from two patients. Isolates from one of the two patients also demonstrated increased ERG11 expression, whereas isolates from the other patient did not. Increased levels ofMDR1 mRNA correlated with increased resistance in sequential isolates from another patient. Initial overexpression ofMDR1 with subsequent overexpression of CDRgenes and a final isolate again overexpressing MDR1 were detected in serial isolates from another patient. In another patient, overexpression of these genes was not detected despite an eightfold increase in fluconazole MIC. In this patient, sequence data of theERG11 gene revealed no point mutations associated with decreased susceptibility. Five different patterns of gene expression were observed in isolates recovered from five patients who developed resistance. Therefore, these experiments demonstrate that a variety of mechanisms or combinations of mechanisms are associated with the development of fluconazole drug resistance. Additional studies are needed to estimate the frequency and clinical impact of these mechanisms of resistance.

scholarly journals Point Mutations in Yeast CBF5 Can Abolish In Vivo Pseudouridylation of rRNA

1999 ◽  
Vol 19 (11) ◽  
pp. 7461-7472 ◽  
Author(s):  
Yeganeh Zebarjadian ◽  
Tom King ◽  
Maurille J. Fournier ◽  
Louise Clarke ◽  
John Carbon
Keyword(s):  
Catalytic Domain ◽  
Sequence Similarity ◽  
Point Mutations ◽  
Rrna Synthesis ◽  
Temperature Sensitive ◽  
In Vitro Mutagenesis ◽  
Sequence Motifs ◽  
Conserved Sequence

ABSTRACT In budding yeast (Saccharomyces cerevisiae), the majority of box H/ACA small nucleolar RNPs (snoRNPs) have been shown to direct site-specific pseudouridylation of rRNA. Among the known protein components of H/ACA snoRNPs, the essential nucleolar protein Cbf5p is the most likely pseudouridine (Ψ) synthase. Cbf5p has considerable sequence similarity to Escherichia coli TruBp, a known Ψ synthase, and shares the “KP” and “XLD” conserved sequence motifs found in the catalytic domains of three distinct families of known and putative Ψ synthases. To gain additional evidence on the role of Cbf5p in rRNA biosynthesis, we have used in vitro mutagenesis techniques to introduce various alanine substitutions into the putative Ψ synthase domain of Cbf5p. Yeast strains expressing these mutatedcbf5 genes in a cbf5Δ null background are viable at 25°C but display pronounced cold- and heat-sensitive growth phenotypes. Most of the mutants contain reduced levels of Ψ in rRNA at extreme temperatures. Substitution of alanine for an aspartic acid residue in the conserved XLD motif of Cbf5p (mutantcbf5D95A) abolishes in vivo pseudouridylation of rRNA. Some of the mutants are temperature sensitive both for growth and for formation of Ψ in the rRNA. In most cases, the impaired growth phenotypes are not relieved by transcription of the rRNA from a polymerase II-driven promoter, indicating the absence of polymerase I-related transcriptional defects. There is little or no abnormal accumulation of pre-rRNAs in these mutants, although preferential inhibition of 18S rRNA synthesis is seen in mutantcbf5D95A, which lacks Ψ in rRNA. A subset of mutations in the Ψ synthase domain impairs association of the altered Cbf5p proteins with selected box H/ACA snoRNAs, suggesting that the functional catalytic domain is essential for that interaction. Our results provide additional evidence that Cbf5p is the Ψ synthase component of box H/ACA snoRNPs and suggest that the pseudouridylation of rRNA, although not absolutely required for cell survival, is essential for the formation of fully functional ribosomes.

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