scholarly journals The increased activity of a transcription factor inhibits autophagy in diabetic embryopathy

2019 ◽  
Vol 220 (1) ◽  
pp. 108.e1-108.e12
Author(s):  
Cheng Xu ◽  
Xi Chen ◽  
E. Albert Reece ◽  
Wenhui Lu ◽  
Peixin Yang
Keyword(s):  
Transcription Factor ◽  
Diabetic Embryopathy ◽  
Increased Activity

scholarly journals Pseudomonas aeruginosa lasR mutant fitness in microoxia is supported by an Anr-regulated oxygen-binding hemerythrin

2020 ◽  
Vol 117 (6) ◽  
pp. 3167-3173 ◽  
Author(s):  
Michelle E. Clay ◽  
John H. Hammond ◽  
Fangfang Zhong ◽  
Xiaolei Chen ◽  
Caitlin H. Kowalski ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Transcription Factor ◽  
Oxygen Binding ◽  
Loss Of Function ◽  
Low Oxygen ◽  
Metabolomics Data ◽  
High Affinity ◽  
Oxygen Conditions ◽  
Increased Activity ◽  
Iron Center

Pseudomonas aeruginosa strains with loss-of-function mutations in the transcription factor LasR are frequently encountered in the clinic and the environment. Among the characteristics common to LasR-defective (LasR−) strains is increased activity of the transcription factor Anr, relative to their LasR+ counterparts, in low-oxygen conditions. One of the Anr-regulated genes found to be highly induced in LasR− strains was PA14_42860 (PA1673), which we named mhr for microoxic hemerythrin. Purified P. aeruginosa Mhr protein contained the predicted di-iron center and bound molecular oxygen with an apparent Kd of ∼1 µM. Both Anr and Mhr were necessary for fitness in lasR+ and lasR mutant strains in colony biofilms grown in microoxic conditions, and the effects were more striking in the lasR mutant. Among genes in the Anr regulon, mhr was most closely coregulated with the Anr-controlled high-affinity cytochrome c oxidase genes. In the absence of high-affinity cytochrome c oxidases, deletion of mhr no longer caused a fitness disadvantage, suggesting that Mhr works in concert with microoxic respiration. We demonstrate that Anr and Mhr contribute to LasR− strain fitness even in biofilms grown in normoxic conditions. Furthermore, metabolomics data indicate that, in a lasR mutant, expression of Anr-regulated mhr leads to differences in metabolism in cells grown on lysogeny broth or artificial sputum medium. We propose that increased Anr activity leads to higher levels of the oxygen-binding protein Mhr, which confers an advantage to lasR mutants in microoxic conditions.

scholarly journals The herpes simplex virus immediate-early protein ICP27 stimulates the transcription of cellular Alu repeated sequences by increasing the activity of transcription factor TFIIIC

1992 ◽  
Vol 284 (3) ◽  
pp. 667-673 ◽  
Author(s):  
K L Jang ◽  
D S Latchman
Keyword(s):  
Transcription Factor ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immediate Early ◽  
Cellular Transcription Factor ◽  
Early Protein ◽  
Simplex Virus ◽  
Cellular Transcription ◽  
Increased Activity ◽  
In Cells

Infection with herpes simplex virus (HSV) results in an increase in the transcription of the endogenous Alu repeated sequence by RNA polymerase III. This effect is also observed in uninfected cells stably transformed with a plasmid expressing the HSV immediate-early protein ICP27 or in cells transfected with the gene encoding this protein. Both uninfected cells expressing ICP27 and cells infected with virus producing functional ICP27 display increased activity of the cellular transcription factor TFIIIC when compared with untreated cells. This increase is not observed, however, in cells infected with a mutant strain of virus which does not produce ICP27. Hence ICP27 induces elevated Alu transcription by activating transcription factor TFIIIC, which is the limiting factor for such transcription. This is the first report of increased activity of a cellular transcription factor during HSV infection, when most cellular gene activity is inhibited.

Foxg1 Directly Represses Dbx1 to Confine the POA and Subsequently Regulate Ventral Telencephalic Patterning

2019 ◽  
Vol 29 (12) ◽  
pp. 4968-4981 ◽  
Author(s):  
Ailing Du ◽  
Xiaojing Wu ◽  
Hanhan Chen ◽  
Qing-Ran Bai ◽  
Xiao Han ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Pattern Formation ◽  
Signaling Pathway ◽  
Early Development ◽  
Sonic Hedgehog ◽  
Preoptic Area ◽  
Shh Signaling ◽  
Cortical Hem ◽  
Increased Activity ◽  
Specific Deletion

Abstract During early development, signaling centers, such as the cortical hem and the preoptic area (POA), are critical for telencephalic patterning. However, the mechanisms underlying the maintenance of signal centers are poorly understood. Here, we report that the transcription factor Foxg1 is required to confine the POA, a resource of Sonic Hedgehog (Shh) that is pivotal for ventral telencephalic development. Cell-specific deletion of Foxg1 achieved by crossing Foxg1fl/fl with Dbx1-cre or Nestin-CreER combined with tamoxifen induction results in a dramatic expansion of the POA accompanied by the significantly increased activity of the Shh signaling pathway. Ventral pattern formation was severely impaired. Moreover, we demonstrated that Foxg1 directly represses Dbx1 to restrict the POA. Furthermore, we found that the ventral pallium was expanded, which might also contribute to the observed patterning defects. These findings will improve our understanding of the maintenance of signal centers and help to elucidate the mechanisms underlying ventral telencephalic patterning.

CCAAT/Enhancer Binding Protein Epsilon Mediates Nicotinamide-Enhanced Clearance of Staphylococcus Aureus Infection

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 925-925
Author(s):  
Nils H. Thoennissen ◽  
Pierre Kyme ◽  
Ching Wen Tseng ◽  
Gabriela B. Iwanski ◽  
Kenichi Shimada ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Transcription Factor ◽  
Immune System ◽  
Human Blood ◽  
Innate Immune System ◽  
Innate Immune ◽  
Aureus Infection ◽  
Enhancer Binding Protein ◽  
Increased Activity

Abstract Abstract 925 Staphylococcus aureus in community and healthcare settings commonly causes serious and potentially life-threatening infections. Widespread use of antibiotics is responsible for the emergence and rapid spread of resistant pathogens, including methicillin-resistant S. aureus (MRSA), and highlights a pressing need for development of novel antimicrobial therapies. The myeloid-specific transcription factor, CCAAT/enhancer binding protein epsilon (C/EBPε) serves as a critical regulator of the terminal differentiation and functional maturation of neutrophils and macrophages, both crucial components of the innate immune system. Comparable to humans with neutrophil specific granule deficiency (SGD) carrying a causative mutation in this transcription factor, we showed that C/EBPε-deficient (C/EBPε—/—) mice were severely affected by in vivo infection with S. aureus. Paradoxically, depletion of the defective neutrophils attenuated disease pathology and even improved the outcome of infection. During subcutaneous infection with S. aureus, C/EBPε—/— mice treated with mouse anti-polymorphonuclear neutrophil antibody showed significantly smaller skin lesions, fewer CFU within the lesion, and reduced systemic spread of bacteria. In addition, whole blood from C/EBPε—/— mice was less effective at killing S. aureus compared to their cell-free plasma. Therefore, ineffective clearance of S. aureus by C/EBPε—/— neutrophils, even compared to extracellular killing mechanisms, likely permitted S. aureus to thrive within neutrophils, which further aggravated the infection. Because C/EBPε plays a critical role in the host immune response against S. aureus infection, we further hypothesized that increased activity of C/EBPε could enhance immune killing of bacteria. Using a zink-inducible expression vector, we induced overexpression of C/EBPε in U937-macrophages, and thereby enhanced bacterial clearance including MRSA by up to 1.5 log10 CFU/mL. Interestingly, we found that the epigenetic modulator, nicotinamide (NAM; vitamin B3), increased activity of C/EBPε as well as downstream antimicrobial targets. Upon exposing bone-marrow derived macrophages or mononuclear cells from wildtype mice to NAM (1 or 10 mM), increased levels of lysine acetylation on core histone H3 were detected at the promoter region of CEBPE. This was associated with elevated mRNA and protein levels of C/EBPε, and increased expression of downstream antimicrobials such as cathelicidin(-related) antimicrobial peptide (CAMP) and Lactoferrin. In an in vitro, as well as in vivo infection model, moderately concentrated NAM enhanced killing of S. aureus by up to 3 log10, but had no effect when administered to C/EBPε-deficient mice. This again points to C/EBPε as an important target to boost killing of bacteria by the innate immune system. Strikingly, and consistent with our murine data, NAM treatment reduced the ability of S. aureus to survive in whole human blood obtained from 12 healthy humans by 2–3 log10. In line with our findings on S. aureus, we were able to demonstrate similar immune boosting effects of NAM in human blood infected with other important human pathogens such as K. pneumoniae and P. aeruginosa. In an age when the number of antibiotics in the pipeline is limited and development of resistance occurs rapidly, use of complementary strategies to antibiotic treatment provides a promising method of limiting development of antibiotic resistance. Here, we demonstrated that C/EBPε is a regulatory factor that critically impacts the host's ability to fight bacterial infections. Compounds exerting modulatory effects on this myeloid-specific transcription factor may emerge as important antimicrobial therapeutics against frequent pathogens such as S. aureus. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Взаимосвязи между продукцией тимозина 1α и состоянием внутриклеточных сигнальных механизмов в мононуклеарных лейкоцитах периферической крови при артериальной гипертензии

2020 ◽  
Author(s):  
A.V. Logatkina ◽  
I.V. Terekhov ◽  
V.S. Nikiforov ◽  
S.S. Bondar
Keyword(s):  
Transcription Factor ◽  
Signaling Pathways ◽  
Protein Kinases ◽  
Intracellular Signaling ◽  
Linear Regression Analysis ◽  
Immunocompetent Cells ◽  
Mononuclear Leukocytes ◽  
Nuclear Transcription Factor ◽  
Stat Signaling ◽  
Increased Activity

Цель - изучение влияния тимозина 1 альфа на состояние внутриклеточных сигнальных механизмов, в частности, на состояние терминальных компонентов MAPK/SAPK и JAK/STAT-сигнальных путей в мононуклеарных лейкоцитах периферической крови у пациентов с артериальной гипертензией. Методика. Методом иммуноферментного анализа в мононуклеарных клетках пациентов определяли уровень фосфорилирования факторов STAT5A, STAT6, ERK1/2, p38, а также содержание ядерного фактора транскрипции NF-κB. Взаимосвязи между исследованными факторами оценивали методом линейного регрессионного анализа. Критериями включения в исследование являлись: возраст 45-55 лет, информированное согласие на участие в исследовании, окружность талии более 80 см у женщин и более 94 см у мужчин, артериальная гипертензия (АД ≥ 140/90 мм рт. ст.), а также уровень С-реактивного белка в сыворотке крови, определяемого высокочувствительным методом, в пределах ≥ 2,5 и <5,0 мг/дл), отсутствие в течение предшествующих 3 мес госпитализации, острых бактериальных и вирусных инфекций. Критериями исключения из исследования являлись обострения воспалительных заболеваний внутренних органов, декомпенсация углеводного обмена, отказ от участия в исследовании. Результаты. Повышение сывороточной концентрации Тα1 ассоциируется с активацией в мононуклеарных клетках факторов STAT5A, STAT6, а также протеинкиназ ERK и p38 и ядерного фактора транскрипции NF-κB. Высокая концентрация Тα1 ассоциировалась с повышением активности ядерного фактора транскрипции NF-κB, STAT6 и ERK. На этом фоне повышенный уровень продукции Тα1 сопровождался усилением активности факторов STAT6, STAT5A, а также протеинкиназ ERK и р38, не влияя при этом на активность NF-κB. Заключение. В физиологических концентрациях (0,9-2,85 пг/мл) Тα1 является иммуномодулятором, регулирующим активность MAPK/SAPK и JAK/STAT сигнальных путей через изменение реактивности иммунокомпетентных клеток к сигналам цитокинов, факторов роста и гормонам, в том числе, лептину, инсулину, соматотропину, не обладая при этом прямым активирующим влиянием на продукцию цитокинов. Полученные результаты позволяют рассматривать Тα1 в качестве иммунотропного регулятора, потенциальные эффекты которого (иммуномодулирующие, либо противовоспалительные) определяются его концентрацией в сыворотке, способствуя либо ограничению, либо прогрессированию иммунометаболических нарушений, лежащих в основе патогенеза атеросклероза и артериальной гипертонии.The aim of this work was to study effects of thymosin 1 alpha on intracellular signaling mechanisms, specifically, the state of terminal components of MAPK/SAPK and JAK/STAT signaling pathways in peripheral blood mononuclear leukocytes of patients with arterial hypertension. Methods. The level of phosphorylation of factors STAT5A, STAT6, ERK1/2, and p38 and the content of the nuclear transcription factor NF-κB were measured using the enzyme immunoassay. Relationship between the studied factors was assessed by the linear regression analysis. Results. The increase in serum Tα1 concentration was associated with activation of STAT5A and STAT6 as well as ERK and p38 protein kinases and the nuclear transcription factor NF-κB in mononuclear cells. A high concentration of Tα1 was associated with increased activity of the nuclear transcription factor NF-κB, STAT6, and ERK. In this process, the increased production of Tα1 was associated with increased activity of STAT6 and STAT5A as well as ERK and p38 protein kinases but with unchanged activity of NF-κB. Conclusion. At physiological concentrations (0.9-2.85 pg/ml), Tα1 is an important immunomodulator that regulates activities of the MAPK SAPK and JAK/STAT signaling pathways, thereby changing responses of immunocompetent cells to signals of cytokines, growth factors, and hormones, including leptin, insulin, and somatotropin without a direct activating effect on cytokine production by immunocompetent cells. The results of the study suggested that Tα1 is an immunomodulator potentially capable of correcting respective immunometabolic disorders in patients with hypertension.

Transcription factor/DNA interactions visualized by electron spectroscopic imaging

1992 ◽  
Vol 50 (1) ◽  
pp. 450-451
Author(s):  
David P. Bazett-Jones ◽  
Mark L. Brown
Keyword(s):  
Transcription Factor ◽  
Dna Sequences ◽  
Transcription Initiation ◽  
Molecular Mechanisms ◽  
Phosphorus Content ◽  
Spectroscopic Imaging ◽  
Electron Spectroscopic Imaging ◽  
Dna Backbone ◽  
Two Parameters ◽  
High Level

A multisubunit RNA polymerase enzyme is ultimately responsible for transcription initiation and elongation of RNA, but recognition of the proper start site by the enzyme is regulated by general, temporal and gene-specific trans-factors interacting at promoter and enhancer DNA sequences. To understand the molecular mechanisms which precisely regulate the transcription initiation event, it is crucial to elucidate the structure of the transcription factor/DNA complexes involved. Electron spectroscopic imaging (ESI) provides the opportunity to visualize individual DNA molecules. Enhancement of DNA contrast with ESI is accomplished by imaging with electrons that have interacted with inner shell electrons of phosphorus in the DNA backbone. Phosphorus detection at this intermediately high level of resolution (≈lnm) permits selective imaging of the DNA, to determine whether the protein factors compact, bend or wrap the DNA. Simultaneously, mass analysis and phosphorus content can be measured quantitatively, using adjacent DNA or tobacco mosaic virus (TMV) as mass and phosphorus standards. These two parameters provide stoichiometric information relating the ratios of protein:DNA content.

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