scholarly journals Respiratory Failure Due to Differentiation Arrest and Expansion of Alveolar Cells following Lung-Specific Loss of the Transcription Factor C/EBPα in Mice

2006 ◽  
Vol 26 (3) ◽  
pp. 1109-1123 ◽  
Author(s):  
Daniela S. Bassères ◽  
Elena Levantini ◽  
Hongbin Ji ◽  
Stefano Monti ◽  
Shannon Elf ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Respiratory Failure ◽  
Leucine Zipper ◽  
Type I ◽  
Type Ii ◽  
Alveolar Cells ◽  
Proliferating Cells ◽  
Therapeutic Benefits ◽  
Factor C

ABSTRACT The leucine zipper family transcription factor CCAAT enhancer binding protein alpha (C/EBPα) inhibits proliferation and promotes differentiation in various cell types. In this study, we show, using a lung-specific conditional mouse model of C/EBPα deletion, that loss of C/EBPα in the respiratory epithelium leads to respiratory failure at birth due to an arrest in the type II alveolar cell differentiation program. This differentiation arrest results in the lack of type I alveolar cells and differentiated surfactant-secreting type II alveolar cells. In addition to showing a block in type II cell differentiation, the neonatal lungs display increased numbers of proliferating cells and decreased numbers of apoptotic cells, leading to epithelial expansion and loss of airspace. Consistent with the phenotype observed, genes associated with alveolar maturation, survival, and proliferation were differentially expressed. Taken together, these results identify C/EBPα as a master regulator of airway epithelial maturation and suggest that the loss of C/EBPα could also be an important event in the multistep process of lung tumorigenesis. Furthermore, this study indicates that exploring the C/EBPα pathway might have therapeutic benefits for patients with respiratory distress syndromes.

A stage-specific functional role of the leucine zipper transcription factor c-Maf in lung Th2 cell differentiation

2004 ◽  
Vol 34 (12) ◽  
pp. 3401-3412 ◽  
Author(s):  
Michael Hausding ◽  
I-Cheng Ho ◽  
Hans?A. Lehr ◽  
B. Weigmann ◽  
Christine Lux ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Functional Role ◽  
Leucine Zipper ◽  
Th2 Cell ◽  
Factor C

scholarly journals β-Catenin/Lin28/let-7 regulatory network determines type II alveolar epithelial stem cell differentiation phenotypes following thoracic irradiation

2020 ◽  
Vol 62 (1) ◽  
pp. 119-132
Author(s):  
Xiaozhuan Liu ◽  
Tingting Zhang ◽  
Jianwei Zhou ◽  
Ziting Xiao ◽  
Yanjun Li ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Stem Cell Differentiation ◽  
Alveolar Epithelial Cells ◽  
Type I ◽  
Type Ii ◽  
Epithelial Stem Cells ◽  
Alveolar Epithelial ◽  
Thoracic Irradiation ◽  
Radiation Induced ◽  
Differentiation Marker

Abstract The contribution of type II alveolar epithelial stem cells (AEC II) to radiation-induced lung fibrosis (RILF) is largely unknown. Cell differentiation phenotypes are determined by the balance between Lin28 and lethal-7 microRNA (let-7 miRNA). Lin28 is activated by β-catenin. The aim of this study was to track AEC II phenotypes at different phases of injury following thoracic irradiation and examine the expression of β-catenin, Lin28 and let-7 to identify their role in AEC II differentiation. Results showed that coexpression of prosurfactant protein C (proSP-C, an AEC II biomarker) and HOPX (homeobox only protein X, an AEC I biomarker) or vimentin (a differentiation marker) was detected in AEC II post-irradiation. The protein expression levels of HOPX and proSP-C were significantly downregulated, but vimentin was significantly upregulated following irradiation. The expression of E-cadherin, which prevents β-catenin from translocating to the nucleus, was downregulated, and the expression of β-catenin and Lin28 was upregulated after irradiation (P < 0.05 to P < 0.001). Four let-7 miRNA members (a, b, c and d) were upregulated in irradiated lungs (P < 0.05 to P < 0.001), but let-7d was significantly downregulated at 5 and 6 months (P < 0.001). The ratios of Lin28 to four let-7 members were low during the early phase of injury and were slightly higher after 2 months. Intriguingly, the Lin28/let-7d ratio was strikingly increased after 4 months. We concluded that β-catenin contributed to RILF by promoting Lin28 expression, which increased the number of AEC II and the transcription of profibrotic molecules. In this study, the downregulation of let-7d miRNA by Lin28 resulted in the inability of AEC II to differentiate into type I alveolar epithelial cells (AEC I).

scholarly journals Downregulation of c-Jun Expression by Transcription Factor C/EBPα Is Critical for Granulocytic Lineage Commitment

2002 ◽  
Vol 22 (24) ◽  
pp. 8681-8694 ◽  
Author(s):  
Janki Rangatia ◽  
Rajani Kanth Vangala ◽  
Nicolai Treiber ◽  
Pu Zhang ◽  
Hanna Radomska ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Knockout Mouse ◽  
Leucine Zipper ◽  
Fetal Liver ◽  
Mrna Level ◽  
Monocytic Differentiation ◽  
Granulocytic Differentiation ◽  
Conditional Expression ◽  
Factor C ◽  
Transcription Factor Complex

ABSTRACT The transcription factor C/EBPα is crucial for the differentiation of granulocytes. Conditional expression of C/EBPα triggers neutrophilic differentiation, and C/EBPα can block 12-O-tetradecanoylphorbol-13-acetate-induced monocytic differentiation of bipotential myeloid cells. In C/EBPα knockout mice, no mature granulocytes are present. A dramatic increase of c-Jun mRNA in C/EBPα knockout mouse fetal liver was observed. c-Jun, a component of the AP-1 transcription factor complex and a coactivator of the transcription factor PU.1, is important for monocytic differentiation. Here we report that C/EBPα downregulates c-Jun expression to drive granulocytic differentiation. An ectopic increase of C/EBPα expression decreases the c-Jun mRNA level, and the human c-Jun promoter activity is downregulated eightfold in the presence of C/EBPα. C/EBPα and c-Jun interact through their leucine zipper domains, and this interaction prevents c-Jun from binding to DNA. This results in downregulation of c-Jun's capacity to autoregulate its own promoter through the proximal AP-1 site. Overexpression of c-Jun prevents C/EBPα-induced granulocytic differentiation. Thus, we propose a model in which C/EBPα needs to downregulate c-Jun expression and transactivation capacity for promoting granulocytic differentiation.

scholarly journals Transcriptome analyses of cells carrying the Type II Csp231I restriction–modification system reveal cross-talk between two unrelated transcription factors: C protein and the Rac prophage repressor

2019 ◽  
Vol 47 (18) ◽  
pp. 9542-9556 ◽  
Author(s):  
Alessandro Negri ◽  
Marcin Jąkalski ◽  
Aleksandra Szczuka ◽  
Leszek P Pryszcz ◽  
Iwona Mruk
Keyword(s):  
Transcription Factor ◽  
Gene Transfer ◽  
Cross Talk ◽  
Dna Cleavage ◽  
In Vitro Assays ◽  
Type Ii ◽  
Modification System ◽  
C Protein ◽  
Factor C ◽  
Restriction Modification

AbstractRestriction-modification (R–M) systems represent an effective mechanism of defence against invading bacteriophages, and are widely spread among bacteria and archaea. In acquiring a Type II R–M system via horizontal gene transfer, the new hosts become more resistant to phage infection, through the action of a restriction endonuclease (REase), which recognizes and cleaves specific target DNAs. To protect the host cell's DNA, there is also a methyltransferase (MTase), which prevents DNA cleavage by the cognate REase. In some R–M systems, the host also accepts a cis-acting transcription factor (C protein), which regulates the counteracting activities of REase and MTase to avoid host self-restriction. Our study characterized the unexpected phenotype of Escherichia coli cells, which manifested as extensive cell filamentation triggered by acquiring the Csp231I R–M system from Citrobacter sp. Surprisingly, we found that the cell morphology defect was solely dependent on the C regulator. Our transcriptome analysis supported by in vivo and in vitro assays showed that C protein directly silenced the expression of the RacR repressor to affect the Rac prophage-related genes. The rac locus ydaST genes, when derepressed, exerted a toxicity indicated by cell filamentation through an unknown mechanism. These results provide an apparent example of transcription factor cross-talk, which can have significant consequences for the host, and may represent a constraint on lateral gene transfer.

scholarly journals Plasticity of Hopx+ type I alveolar cells to regenerate type II cells in the lung

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Rajan Jain ◽  
Christina E. Barkauskas ◽  
Norifumi Takeda ◽  
Emily J. Bowie ◽  
Haig Aghajanian ◽  
...  
Keyword(s):  
Type I ◽  
Type Ii Cells ◽  
Type Ii ◽  
Alveolar Cells

Pharmacological Foundations of Cannabis Chemovars

Planta Medica ◽  
2017 ◽  
Vol 84 (04) ◽  
pp. 225-233 ◽  
Author(s):  
Mark Lewis ◽  
Ethan Russo ◽  
Kevin Smith
Keyword(s):  
Short Term Memory ◽  
Symptomatic Relief ◽  
Breeding Program ◽  
Type I ◽  
Type Ii ◽  
Short Term ◽  
Content Type ◽  
Therapeutic Benefits ◽  
Predominant Type ◽  
Chemical Profiles

AbstractAn advanced Mendelian Cannabis breeding program has been developed utilizing chemical markers to maximize the yield of phytocannabinoids and terpenoids with the aim to improve therapeutic efficacy and safety. Cannabis is often divided into several categories based on cannabinoid content. Type I, Δ 9-tetrahydrocannabinol-predominant, is the prevalent offering in both medical and recreational marketplaces. In recent years, the therapeutic benefits of cannabidiol have been better recognized, leading to the promotion of additional chemovars: Type II, Cannabis that contains both Δ 9-tetrahydrocannabinol and cannabidiol, and cannabidiol-predominant Type III Cannabis. While high-Δ 9-tetrahydrocannabinol and high-myrcene chemovars dominate markets, these may not be optimal for patients who require distinct chemical profiles to achieve symptomatic relief. Type II Cannabis chemovars that display cannabidiol- and terpenoid-rich profiles have the potential to improve both efficacy and minimize adverse events associated with Δ 9-tetrahydrocannabinol exposure. Cannabis samples were analyzed for cannabinoid and terpenoid content, and analytical results are presented via PhytoFacts, a patent-pending method of graphically displaying phytocannabinoid and terpenoid content, as well as scent, taste, and subjective therapeutic effect data. Examples from the breeding program are highlighted and include Type I, II, and III Cannabis chemovars, those highly potent in terpenoids in general, or single components, for example, limonene, pinene, terpinolene, and linalool. Additionally, it is demonstrated how Type I – III chemovars have been developed with conserved terpenoid proportions. Specific chemovars may produce enhanced analgesia, anti-inflammatory, anticonvulsant, antidepressant, and anti-anxiety effects, while simultaneously reducing sequelae of Δ 9-tetrahydrocannabinol such as panic, toxic psychosis, and short-term memory impairment.

In vivo exposure to hyperoxia induces DNA damage in a population of alveolar type II epithelial cells

2004 ◽  
Vol 286 (5) ◽  
pp. L1045-L1054 ◽  
Author(s):  
Jason M. Roper ◽  
Dawn J. Mazzatti ◽  
Richard H. Watkins ◽  
William M. Maniscalco ◽  
Peter C. Keng ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Transmembrane Protein ◽  
Dna Integrity ◽  
Alveolar Type ◽  
Type I ◽  
Type Ii Cells ◽  
Type Ii ◽  
Alveolar Cells ◽  
Endogenous Expression

It is well established that hyperoxia injures and kills alveolar endothelial and type I epithelial cells of the lung. Although type II epithelial cells remain morphologically intact, it remains unclear whether they are also damaged. DNA integrity was investigated in adult mice whose type II cells were identified by their endogenous expression of pro-surfactant protein C or transgenic expression of enhanced green fluorescent protein. In mice exposed to room air, punctate perinuclear 8-oxoguanine staining was detected in ∼4% of all alveolar cells and in 30% of type II cells. After 48 or 72 h of hyperoxia, 8-oxoguanine was detected in 11% of all alveolar cells and in >60% of type II cells. 8-Oxoguanine colocalized by confocal microscopy with the mitochondrial transmembrane protein cytochrome oxidase subunit 1. Type II cells isolated from hyperoxic lungs exhibited nuclear DNA strand breaks by comet assay even though they were viable and morphologically indistinguishable from cells isolated from lungs exposed to room air. These data reveal that type II cells exposed to in vivo hyperoxia have oxidized and fragmented DNA. Because type II cells are essential for lung remodeling, our findings raise the possibility that they are proficient in DNA repair.

Congenital diaphragmatic hernia, tracheal occlusion, thyroid transcription factor-1, and fetal pulmonary epithelial maturation

2005 ◽  
Vol 289 (1) ◽  
pp. L44-L52 ◽  
Author(s):  
Cheryl J. Chapin ◽  
Robert Ertsey ◽  
Jyoji Yoshizawa ◽  
Akihiko Hara ◽  
Lourenco Sbragia ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dna Content ◽  
Pulmonary Hypoplasia ◽  
Alveolar Type ◽  
Type I ◽  
Type Ii ◽  
Lung Growth ◽  
Thyroid Transcription Factor 1 ◽  
Thyroid Transcription Factor ◽  
Transcription Factor 1

Congenital diaphragmatic hernia (CDH) occurs in ∼1:2,500 human births and has high morbidity and mortality rates, primarily due to pulmonary hypoplasia and pulmonary hypertension. Tracheal occlusion (TO), in experimental animals, distends lungs and increases lung growth and alveolar type I cell maturation but decreases surfactant components and reduces alveolar type II cell density. We examined effects of CDH and CDH+TO on lung growth and maturation in fetal rats. To induce CDH, we administered nitrofen (100 mg) to dams at 9.5 days of gestation. We compared lungs from fetuses with CDH, CDH+TO, and those exposed to nitrofen without CDH. CDH decreased lung wet weight bilaterally ( P < 0.0001) and DNA content in lung ipsilateral to CDH ( P < 0.05). CDH+TO significantly increased lung wet weights bilaterally; DNA content was intermediate between CDH and NC. To evaluate effects on the distal pulmonary epithelium, we examined surfactant mRNA and protein levels, type I and II cell-specific markers (RTI40 and RTII70, respectively), and transcriptional regulator thyroid transcription factor-1 (TTF-1). Decreased lung distension (due to CDH) increased SP-C mRNA and TTF-1 protein expression and reduced RTI40 ( P < 0.05 for all). Increased lung distension (due to CDH+TO) reduced expression of SP mRNAs and pro-SP-C and TTF-1 proteins and enhanced expression of RTI40 (mRNA and protein; P < 0.05 for all). We conclude that CDH+TO partially reverses effects of CDH; it corrects the pulmonary hypoplasia and restores type I cell differentiation but adversely affects SP expression in type II cells. These effects may be mediated through changes in TTF-1 expression.

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