Vasoactive intestinal peptide upregulates MUC2 intestinal mucin via CREB/ATF1

Hokari, Ryota; Lee, Hwa Young; Crawley, Suzanne C.; Yang, Stacey C.; Gum, James R.; Miura, Soichiro; Kim, Young S.

doi:10.1152/ajpgi.00142.2005

Cited by 58 publications

(37 citation statements)

References 83 publications

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“…GATA2/3/4, Cdx-1, AP-1 and MAF seem to be of particular importance as their binding sites are uniquely present in both the differentially active promoter fragments (Table 1). Involvement of these transcription factors in mediating cancer cell signaling and/or mucin gene expression has been demonstrated in previous studies (Dhakshinamoorthy and Jaiswal, 2002;Chen et al, 2004;Guo et al, 2004;Hokari et al, 2005) and should further be explored for the regulation of MUC4 expression. Stability of the protein is determined by certain inherent (structural) and external factors.…”

Section: Discussionmentioning

confidence: 78%

MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms

et al. 2006

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MUC4 mucin is a high molecular weight transmembrane glycoprotein that plays important roles in tumour biology. It is aberrantly expressed in pancreatic adenocarcinoma, while not being detectable in the normal pancreas. Previous studies have demonstrated that the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that is defective in CF, is implicated in multiple cellular functions, including gene regulation. In the present study, using a CFTR-defective pancreatic cancer cell line and its derived subline expressing functional CFTR, we report that MUC4 expression is negatively regulated by CFTR. Short-interfering RNA (siRNA)-mediated silencing of CFTR also leads to an increased expression of MUC4. Additionally, our results suggest that CFTR-mediated regulation of MUC4 is cell densitydependent and is achieved by transcriptional and posttranslational mechanisms. Moreover, in a panel of pancreatic cancer cell lines and normal pancreas, we observed that CFTR was downregulated in pancreatic cancer cells and negatively correlated with MUC4 in most cases. An aberrant expression of MUC4 was also detected in the CF pancreas. Downregulation of CFTR in pancreatic adenocarcinoma and its inverse association with the tumour-linked mucin, MUC4, indicate novel function(s) of CFTR in pancreatic tumour biology and suggest the implication of new signalling pathway(s) in MUC4 regulation.

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Section: Discussionmentioning

confidence: 78%

MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms

et al. 2006

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“…However, this decrease may not be dependent on CREB. In addition to its role as a CREB inhibitor, H89 has also been shown to play a role in the inhibition of mitogen stress kinase 1 (MSK1) (16,48), which phosphorylates NF-B to induce NF-B-mediated gene transcription (48). To test whether this effect was relevant, we tested but did not find any indication of MSK1 phosphorylation or NF-B phosphorylation in any of our samples OMVs.…”

Section: Discussionmentioning

confidence: 94%

Context-Dependent Activation Kinetics Elicited by Soluble versus Outer Membrane Vesicle-Associated Heat-Labile Enterotoxin

Chutkan

Kuehn

2011

Infect Immun

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Enterotoxigenic Escherichia coli (ETEC) is the leading cause of traveler's diarrhea and children's diarrhea worldwide. Among its virulence factors, ETEC produces heat-labile enterotoxin (LT). Most secreted LT is associated with outer membrane vesicles that are rich in lipopolysaccharide. The majority of prior studies have focused on soluble LT purified from ETEC periplasm. We investigated the hypothesis that the extracellular vesicle context of toxin presentation might be important in eliciting immune responses. We compared the polarized epithelial cell responses to apically applied soluble LT and LT-containing vesicles (LT ؉ vesicles) as well as controls using a catalytically inactive mutant of LT and vesicles lacking LT. Although vesicle treatments with no or catalytically inactive LT induced a modest amount of interleukin-6 (IL-6), samples containing catalytically active LT elicited higher levels. A combination of soluble LT and LT-deficient vesicles induced significantly higher IL-6 levels than either LT or LT ؉ vesicles alone. The responses to LT ؉ vesicles were found to be independent of the canonical LT pathway, because the inhibition of cyclic AMP response element (CRE)-binding protein (CREB) phosphorylation did not lead to a decrease in cytokine gene expression levels. Furthermore, soluble LT caused earlier phosphorylation of CREB and activation of CRE compared with LT ؉ vesicles. Soluble LT also led to the activation of activator protein 1, whereas LT ؉ vesicle IL-6 responses appeared to be mediated by NF-B. In summary, the results demonstrate that soluble LT and vesicle-bound LT elicit ultimately similar cytokine responses through distinct different activation pathways.Enterotoxigenic Escherichia coli (ETEC) is the leading cause of traveler's diarrhea (3), and it has been estimated to cause approximately 10 million cases of traveler's diarrhea worldwide (45). ETEC is also the leading cause of morbidity and mortality due to diarrhea in children in developing countries. A total of 280 million cases of diarrhea associated with ETEC were found in children less than 5 years old in outpatient clinics in developing countries (50), and mortality due to ETEC has been estimated at 170,000 deaths annually (32). Heat-labile enterotoxin (LT) is a major virulence factor produced by ETEC and is known to contribute to the disease (20).LT is an AB5 toxin that is composed of a pentameric B subunit, which binds to host receptors, and a catalytically active A subunit (12). The B pentameric ring binds to the Gal␤1,3GalNAc␤1(NeuAc␣2,3),4Gal␤1,4Glc ceramide (G M1 ) ganglioside on host cells, which mediates internalization. Studies using soluble LT that was purified from the periplasm have led to a detailed understanding of its complex trafficking pathway and activation inside mammalian cells (12,20,39). Once internalized, LT is trafficked to the Golgi apparatus and the endoplasmic reticulum (ER), where the A subunit is further processed. The modified A subunit then catalyzes ADP-ribosylation of the Gs␣ subunit in the adenyl...

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“…VIP has the ability to differentially induce cAMP-dependent and -independent signaling pathways, with a predilection that is partly determined by cell type. PKA, PKC, or both (9,27), as well as the downstream MAP kinase cascade (81), can be involved in signal transduction. VIP acts via CREB and/or Ets family members to stimulate target gene expression (15,27,81).…”

Section: Discussionmentioning

confidence: 99%

“…PKA, PKC, or both (9,27), as well as the downstream MAP kinase cascade (81), can be involved in signal transduction. VIP acts via CREB and/or Ets family members to stimulate target gene expression (15,27,81). Binding sites for both types of transcription factors are located in the HCMV MIE enhancer/promoter (57).…”

Section: Discussionmentioning

confidence: 99%

“…While VIP's effect on NT2 cells has not been reported, VIP is known to activate target cellular genes through signaling pathways that involve PKA, PKC, or both, depending on cell type (9,27). The type of stimulus and the cellular phenotype determine whether PKA (64) or PKC (30,77) acts through the CRE to increase MIE enhancer/ promoter activity in transient assays.…”

Section: Vip Activates Hcmv Mie Gene Expressionmentioning

confidence: 99%

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Breaking Human Cytomegalovirus Major Immediate-Early Gene Silence by Vasoactive Intestinal Peptide Stimulation of the Protein Kinase A-CREB-TORC2 Signaling Cascade in Human Pluripotent Embryonal NTera2 Cells

Yuan

Liu

et al. 2009

J Virol

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. We speculate that neurohormonal stimulation via this signaling cascade is a possible means for reversing HCMV silence in vivo.Persons with impaired cellular immunity risk tissue-invasive disease from reactivation of latent human cytomegalovirus (HCMV). HCMV reactivation in tissues or blood of immunocompetent patients suffering illness from another cause also occurs but usually goes unnoticed and is self-limiting. For instance, nearly one-third of patients who are critically ill or in septic shock have detectable findings of HCMV reactivation in their bloodstream (12,26,43,45,80). HCMV reactivation infection in intestinal tissues with preexisting inflammatory disease (e.g., inflammatory bowel disease) is also well described for immunocompetent patients (28,39,40,51). The precise triggering mechanisms that underlie HCMV reactivation are unknown.So far, only cells of myeloid lineage have been determined to fulfill criteria for cellular sites of HCMV latency in vivo. In healthy HCMV-seropositive persons, precursors of macrophages and dendritic cells, including CD34ϩ hematopoietic progenitor cells, carry latent HCMV genomes at a low frequency (75). The terminal differentiation of these cells into a macrophage-or dendritic cell-like phenotype is a prerequisite for HCMV reactivation ex vivo (67, 76). However, this reactivation appears to be a rare event, suggesting that other, as yet unidentified factors may promote HCMV reactivation. Stimulation with tumor necrosis factor alpha (TNF-␣) or gamma interferon may promote HCMV reactivation from differentiated counterparts of monocytic-dendritic cell precursors that had been infected latently in vitro or in vivo (25,66,67,76).For both HCMV and murine CMV, viral major immediateearly (MIE) gene expression is greatly restricted or shut off during viral latency, and the productive viral life cycle cannot advance without this expression (57,74,75,78). The MIE enhancer/promoter controlling expression is regulated by the coordinated actions of multiple types of cis-acting elements (57). These elements are bound by cellular transcription factors whose functions are modulated by input supplied by the cell, the virus, and the external surrounding (57). Higher-order chromatin structure contributes to this regulation. Heterochromatin components amass on the inactive MIE enhancer/promoter in viral latency, whereas the chromatin signatures of transcriptional activity predominate at the active MIE enhancer/ promoter in acute and reactivation infections (47,67). MIE enhancer/promoter silencing is also favored by innate antiviral mechanisms that partly involve the repressive actions of nuclear ND10 domain components (e.g., hDAXX, PML, ATRX, and histone deacetylase [HDAC]) (52) but does not involve CpG methylation of the MIE enhancer/promoter (29).Quiescent HCMV infection of human NTera2/D1 cells (NT2 cells) is a tractable model system for studying the regulation of HCMV MIE enhancer/promoter reactivation (37, 54). NT2 cells share many phenotypic features with pluripotent

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Vasoactive intestinal peptide upregulates MUC2 intestinal mucin via CREB/ATF1

Cited by 58 publications

References 83 publications

MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms

MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms

Context-Dependent Activation Kinetics Elicited by Soluble versus Outer Membrane Vesicle-Associated Heat-Labile Enterotoxin

Breaking Human Cytomegalovirus Major Immediate-Early Gene Silence by Vasoactive Intestinal Peptide Stimulation of the Protein Kinase A-CREB-TORC2 Signaling Cascade in Human Pluripotent Embryonal NTera2 Cells

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