Sp1 up-regulates cAMP-response-element-binding protein expression during retinoic acid-induced mucous differentiation of normal human bronchial epithelial cells

Hong, Joon Seok; Kim, Seung Wook; Koo, Ja Seok

doi:10.1042/bj20070904

Cited by 12 publications

(8 citation statements)

References 55 publications

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“…Supporting this inference, the Munc18b promoter contains binding sites for transcription factors known to be important in airway epithelial development (Supplementary Figure S3). These include GRE, CRE and GATA sites, consistent with the well-known role of glucocorticosteroids in lung epithelial secretory cell development [ 55 ], the importance of CREB (cAMP-response-element-binding protein) in mucociliary differentiation of airway epithelium in response to retinoids [ 56 , 57 ] and the requirement for GATA-6 in development of the bronchiolar epithelium [ 55 – 57 ]. The promoter also contains an E-box that binds bHLH transcription factors required for development of a secretory phenotype in gut epithelium [ 49 ], and an Ets motif that could interact with SPDEF (SAM-pointed-domain-containing Ets factor), which co-activates the expression of multiple lung epithelial genes [ 55 ].…”

Section: Discussionmentioning

confidence: 78%

Munc18b is an essential gene in mice whose expression is limiting for secretion by airway epithelial and mast cells

Kim

Petrova

Scott

et al. 2012

Biochemical Journal

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Airway mucin secretion and MC (mast cell) degranulation must be tightly controlled for homoeostasis of the lungs and immune system respectively. We found the exocytic protein Munc18b to be highly expressed in mouse airway epithelial cells and MCs, and localized to the apical pole of airway secretory cells. To address its functions, we created a mouse with a severely hypomorphic Munc18b allele such that protein expression in heterozygotes was reduced by ~50%. Homozygous mutant mice were not viable, but heterozygotes showed a ~50% reduction in stimulated release of mucin from epithelial cells and granule contents from MCs. The defect in MCs affected only regulated secretion and not constitutive or transporter-mediated secretion. The severity of passive cutaneous anaphylaxis was also reduced by ~50%, showing that reduction of Munc18b expression results in an attenuation of physiological responses dependent on MC degranulation. The Munc18b promoter is controlled by INR (initiator), Sp1 (specificity protein 1), Ets, CRE (cAMP-response element), GRE (glucocorticoid-response element), GATA and E-box elements in airway epithelial cells; however, protein levels did not change during mucous metaplasia induced by allergic inflammation. Taken together, the results of the present study identify Munc18b as an essential gene that is a limiting component of the exocytic machinery of epithelial cells and MCs.

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Section: Discussionmentioning

confidence: 78%

Munc18b is an essential gene in mice whose expression is limiting for secretion by airway epithelial and mast cells

Kim

Petrova

Scott

et al. 2012

Biochemical Journal

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“…SP1, CEBPA, and ETS1 were connected to serous cell LTF and LYZ, and played roles in modulation of extracellular matrix components for bronchial repair and metastasis. 50 As suggested by its origin as a B-lymphocyte transcription factor, NFKB1 regulated serous cell PIGR and IGHA1 and IGHA2 expression.…”

Section: Resultsmentioning

confidence: 99%

Protein networks in induced sputum from smokers and COPD patients

Baraniuk¹,

Casado²,

Pannell³

et al. 2015

COPD

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RationaleSubtypes of cigarette smoke-induced disease affect different lung structures and may have distinct pathophysiological mechanisms.ObjectiveTo determine if proteomic classification of the cellular and vascular origins of sputum proteins can characterize these mechanisms and phenotypes.Subjects and methodsIndividual sputum specimens from lifelong nonsmokers (n=7) and smokers with normal lung function (n=13), mucous hypersecretion with normal lung function (n=11), obstructed airflow without emphysema (n=15), and obstruction plus emphysema (n=10) were assessed with mass spectrometry. Data reduction, logarithmic transformation of spectral counts, and Cytoscape network-interaction analysis were performed. The original 203 proteins were reduced to the most informative 50. Sources were secretory dimeric IgA, submucosal gland serous and mucous cells, goblet and other epithelial cells, and vascular permeability.ResultsEpithelial proteins discriminated nonsmokers from smokers. Mucin 5AC was elevated in healthy smokers and chronic bronchitis, suggesting a continuum with the severity of hypersecretion determined by mechanisms of goblet-cell hyperplasia. Obstructed airflow was correlated with glandular proteins and lower levels of Ig joining chain compared to other groups. Emphysema subjects’ sputum was unique, with high plasma proteins and components of neutrophil extracellular traps, such as histones and defensins. In contrast, defensins were correlated with epithelial proteins in all other groups. Protein-network interactions were unique to each group.ConclusionThe proteomes were interpreted as complex “biosignatures” that suggest distinct pathophysiological mechanisms for mucin 5AC hypersecretion, airflow obstruction, and inflammatory emphysema phenotypes. Proteomic phenotyping may improve genotyping studies by selecting more homogeneous study groups. Each phenotype may require its own mechanistically based diagnostic, risk-assessment, drug- and other treatment algorithms.

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“…2,8,39,40 In addition, there are genes that are modulated indirectly by transcription factors that are themselves true direct targets of retinoic acid such as HOX genes, AP2, EGR1 and ID1, 12 or transcription factors that are regulated post-transcriptionally by retinoic acid such as AP1, [41][42][43] or CREB. 13,44 was also conserved in other species yet it was not functional in the UMSCC 22B cells. The reason for the difference in the function of these two potential nuclear receptor-binding sites (DR5II and DR5III) is not clear.…”

Section: Identification Of Rare In Gprc5a Promotermentioning

confidence: 97%

Mechanisms underlying the induction of the putative human tumor suppressor GPRC5A by Retinoic acid

Tao²,

Wang³

et al. 2009

Cancer Biology & Therapy

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Retinoic acid regulates the expression of genes involved in cell proliferation, differentiation and survival by direct control of gene transcription via activation of nuclear retinoid receptors bound to response elements in the promoters of target genes or by indirect mechanisms. Herein, we investigated the mechanism by which retinoic acid induces the expression of the human tumor suppressor GPRC5A. The proximal 5' upstream region of the GPRC5A gene was found to contain two potential RAR/RXR binding sites (RAREs) and one VDR/RXR binding site with direct repeat 5 (DR5) motifs designated DR5I (-489 to -473), DR5II (-136 to -120) and DR5III (-81 to -65). DR5II and DR5III but not DR5I were conserved among vertebrates. However, only DR5III (5'-TGT CCC TCT GCT CAC CC-3') was found to be the functional RARE for mediating induction of GPRC5A as indicated by electrophoretic mobility shift assay using wild type and mutated synthetic oligonucleotides representing different fragments of the promoter for competition with retinoic acid receptor beta RARE. Chromatin immunoprecipitation assay confirmed the binding of retinoic acid receptors alpha and gamma and retinoid X receptors alpha and beta to DR5III in intact cells. These results demonstrate the importance of functional analysis for validating the activity of predicted response elements.

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Sp1 up-regulates cAMP-response-element-binding protein expression during retinoic acid-induced mucous differentiation of normal human bronchial epithelial cells

Cited by 12 publications

References 55 publications

Munc18b is an essential gene in mice whose expression is limiting for secretion by airway epithelial and mast cells

Munc18b is an essential gene in mice whose expression is limiting for secretion by airway epithelial and mast cells

Protein networks in induced sputum from smokers and COPD patients

Mechanisms underlying the induction of the putative human tumor suppressor GPRC5A by Retinoic acid

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