Mechanisms elevating ORMDL3 expression in recurrent wheeze patients: Role of Ets-1, p300 and CREB

Jin, Rui; Xu, Hua‐Guo; Yuan, Weiwei; Zhuang, Lili; Liu, Lifei; Jiang, Li; Zhu, Liang‐Hua; Liu, Jiayin; Zhou, Guoping

doi:10.1016/j.biocel.2012.04.007

Cited by 27 publications

(24 citation statements)

References 37 publications

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“…Our findings run partly counter to two reports, one showing an increase of pulmonary phosphorylated (p)CREB in adult steroid-resistant or untreated asthma25, and the other reporting an increase of total CREB in peripheral blood of patients with recurrent wheeze46. However, in a novel analysis of published gene expression data (DEGAS = DysrEgulated Gene set Analysis via Subnetworks) with the aim to identify subnetworks and dysregulated pathways in diseases, CREB1 was listed as down-regulated in airway epithelial cells of patients with asthma, confirming our finding from primary NHBE cells4748.…”

Section: Discussioncontrasting

confidence: 99%

Pulmonary microRNA profiles identify involvement of Creb1 and Sec14l3 in bronchial epithelial changes in allergic asthma

Bartel

Alessandrini

et al. 2017

Sci Rep

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Asthma is highly prevalent, but current therapies cannot influence the chronic course of the disease. It is thus important to understand underlying early molecular events. In this study, we aimed to use microRNAs (miRNAs) - which are critical regulators of signaling cascades - to identify so far uncharacterized asthma pathogenesis pathways. Therefore, deregulation of miRNAs was assessed in whole lungs from mice with ovalbumin (OVA)-induced allergic airway inflammation (AAI). In silico predicted target genes were confirmed in reporter assays and in house-dust-mite (HDM) induced AAI and primary human bronchial epithelial cells (NHBE) cultured at the air-liquid interface. We identified and validated the transcription factor cAMP-responsive element binding protein (Creb1) and its transcriptional co-activators (Crtc1-3) as targets of miR-17, miR-144, and miR-21. Sec14-like 3 (Sec14l3) - a putative target of Creb1 - was down-regulated in both asthma models and in NHBE cells upon IL13 treatment, while it’s expression correlated with ciliated cell development and decreased along with increasing goblet cell metaplasia. Finally, we propose that Creb1/Crtc1-3 and Sec14l3 could be important for early responses of the bronchial epithelium to Th2-stimuli. This study shows that miRNA profiles can be used to identify novel targets that would be overlooked in mRNA based strategies.

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Section: Discussioncontrasting

confidence: 99%

Pulmonary microRNA profiles identify involvement of Creb1 and Sec14l3 in bronchial epithelial changes in allergic asthma

Bartel

Alessandrini

et al. 2017

Sci Rep

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“…Firstly, in vitro study of the ORMDL3 promoter revealed that Est-1, p300, and CREB are regulators of ORMDL3 expression and that the levels of these regulators correlated with expression of ORMDL3 in recurrent wheeze patients (43). Later, STAT6 was shown to be a direct regulator of ORMDL3 expression (44), confirming previous findings that both ORMDL3 and STAT6 are associated with asthma (45).…”

Section: Association Of Ormdl3 With Asthma and Other Pathologiessupporting

confidence: 76%

The role of ORMDL proteins, guardians of cellular sphingolipids, in asthma

Paulenda

Dráber

2016

Allergy

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To cite this article: Paulenda T, Draber P. The role of ORMDL proteins, guardians of cellular sphingolipids, in asthma. AbstractA family of widely expressed ORM-like (ORMDL) proteins has been recently linked to asthma in genomewide association studies in humans and extensively explored in in vivo studies in mice. ORMDL proteins are key regulators of serine palmitoyltransferase, an enzyme catalyzing the initial step of sphingolipid biosynthesis. Sphingolipids play prominent roles in cell signaling and response to stress, and they affect the mechanistic properties of cellular membranes. Deregulation of sphingolipid biosynthesis and their recycling has been proven to support and even cause several diseases including allergy, inflammation, and asthma. ORMDL3, the most extensively studied member of the ORMDL family, has been shown to be important for endoplasmic reticulum homeostasis by regulating the unfolded protein response and calcium response. In immune cells, ORMDL3 is involved in migration and in the production of proinflammatory cytokines. Furthermore, changes in the expression level of ORMDL3 are important in allergen-induced asthma pathologies. This review focuses on functional aspects of the ORMDL family proteins, which may serve as new therapeutic targets for the treatment of asthma and some other life-threatening diseases.

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“…None of the ORMDL mRNA levels changed significantly after tetracycline-induction of SPT and transcriptional regulation has only been reported for ORMDL3 (7,8,22,23), making it unlikely that a common transcriptional mechanism can account for the regulation we have observed. One possible explanation for these results is that regulation involves alternative splicing or modulation of translational efficiency.…”

Section: Discussionmentioning

confidence: 60%

Expression of the ORMDLS, Modulators of Serine Palmitoyltransferase, Is Regulated by Sphingolipids in Mammalian Cells

Gupta¹,

Gable²,

Alexaki

et al. 2015

Journal of Biological Chemistry

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Background:In contrast to their yeast orthologues, the mechanism by which mammalian ORMDLs regulate serine palmitoyltransferase is not understood. Results: Overexpression of serine palmitoyltransferase in HEK293 cells results in increased long-chain base synthesis and an activity-dependent increase in ORMDL expression. Conclusion: A product of ceramide synthase mediates regulation of ORMDL expression and inhibition of serine palmitoyltransferase. Significance: Serine palmitoyltransferase activity indirectly regulates ORMDL expression.

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Mechanisms elevating ORMDL3 expression in recurrent wheeze patients: Role of Ets-1, p300 and CREB

Cited by 27 publications

References 37 publications

Pulmonary microRNA profiles identify involvement of Creb1 and Sec14l3 in bronchial epithelial changes in allergic asthma

Pulmonary microRNA profiles identify involvement of Creb1 and Sec14l3 in bronchial epithelial changes in allergic asthma

The role of ORMDL proteins, guardians of cellular sphingolipids, in asthma

Expression of the ORMDLS, Modulators of Serine Palmitoyltransferase, Is Regulated by Sphingolipids in Mammalian Cells

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