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Relationship: 987

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Activation, Sp1 leads to Increase, Mucin production

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed Low

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adult Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Sp1 can be phosphorylated by many kinases, resulting in its translocation to the nucleus where it then binds and activates promoters of  various genes to induce their expression. Sp1 activation was shown to result in MUC5AC expression through EGFR/MAPK activation in human airway epithelial cells following stimulation with EGFR ligands (Perrais et al., 2002) or PMA (Hewson et al. 2004), and in a mouse influenza model (Barbier et al., 2012). In addition, increased Sp1 expression and nuclear translocation, resulting in enhanced Sp1-DNA binding and promoter transactivation through two in cis-elements, and ultimately leading to increased expression of MUC5AC, was shown in airway epithelial cells treated with cigarette smoke extract (Di et al., 2012).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

MUC5AC expression can be induced by a variety of inflammatory mediators and growth factors, endotoxins, lipid products and hormones (van Seuningen et al., 2001). The transcription factor Sp1 has long been recognized for its role in regulating expression of mucin genes.

Confirmatory evidence for the involvement of Sp1 in MUC5AC transcription comes from electrophoretic mobility shift assay (EMSA), site-directed mutagenesis and chromosome immunoprecipitation (CHIP) experiments (Hewson et al., 2004; Di et al., 2012). These studies also show that pretreatment of cells with mithramycin A, an antibiotic that specifically blocks Sp1 binding to GC-rich recognition sequences, can suppress or abolish induced MUC5AC transcription.

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Multiple studies have shown that there are Sp1 binding sites in mucin gene promoters, including those of the MUC5AC, MUC5B and MUC2 genes, and that deleting or blocking those binding sites reduces mucin gene and protein expression (Perrais et al., 2002; Hewson et al., 2004; Barbier et al., 2012) and human bronchial epithelial cells (Lee et al., 2011; Wu et al., 2007).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

The MUC5AC promoter has multiple transcription factor binding sites. Therefore, it is likely that alternative pathways contribute to increased mucin production such as activation of HIF-1α or decreased FOXA2 expression (Hao et al., 2014; Kim et al., 2014; Wan et al., 2004).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Unknown

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

Treatment of primary or immortalized bronchial epithelial cells with 10 nM TCDD increased MUC5AC expression in a time-dependent fashion and significantly so after 24 and 48 hours (three- to sevenfold, respectively). A similar behavior was noted for MUC5AC protein expression, and the effect of TCDD was subsequently linked to time-dependent activation of the MUC5AC promoter (reporter gene assay). TCDD was also found to increase Sp1 phosphorylation ca. 1.3-fold at 4-6 hours of treatment (Lee et al., 2012).

Sp1 expression in A549 cells was increased by approx. 2.5-fold following treatment with cigarette smoke extract for 2 hours, and Sp1 nuclear translocation was confirmed by immunostaining. Furthermore, Sp1-DNA complex formation was sigificantly increased in treated compared with untreated cells, with binding to the Sp1B cis element occurring slightly earlier (0.5 hours) than binding to the Sp1A cis element (2 hours); however, quantitative evidence from the EMSA and CHIP experiments was not provided in this report. Additional reporter gene assay data showed that MUC5AC gene expression increased more than 6-fold in the presence of an Sp1-expressing vector following stimulation with 3% cigarette smoke extract  (Di et al., 2012).

Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Lee et al. (2012) reported maximal Sp1 phosphorylation within 4-6 hours and maximal MUC5AC promoter activity at 6-12 hours after stimulation of human bronchial epithelial cells with 10 nM TCDD.

Another study in A549 cells showed increased Sp1 expression and nuclear transloaction at 2 hours, significantly increased binding to the Sp1B cis element at 0.5 and to the Sp1A cis element at 2 hours, and maximally increased MUC5AC expression at 2 to 4 hours of treatment with 3% cigarette smoke extract (Di et al., 2012).

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Unknown

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The available evidence is restricted to human cells.

References

List of the literature that was cited for this KER description. More help

Barbier, D., Garcia-Verdugo, I., Pothlichet, J., Khazen, R., Descamps, D., Rousseau, K., Thornton, D., Si-Tahar, M., Touqui, L., Chignard, M., et al. (2012). Influenza A Induces the Major Secreted Airway Mucin MUC5AC in a Protease–EGFR–Extracellular Regulated Kinase–Sp1–Dependent Pathway. Am J Respir Cell Mol Biol 47, 149–157.

Di, Y.P., Zhao, J., and Harper, R. (2012). Cigarette smoke induces MUC5AC protein expression through the activation of Sp1. J Biol Chem 287, 27948-27958.

Hao, Y., Kuang, Z., Jing, J., Miao, J., Mei, L.Y., Lee, R.J., Kim, S., Choe, S., Krause, D.C., and Lau, G.W. (2014). Mycoplasma pneumoniae modulates STAT3-STAT6/EGFR-FOXA2 signaling to induce overexpression of airway mucins. Infection and Immunity 82, 5246-5255.

Hewson, C., Edbrooke, M., and Johnston, S. (2004). PMA induces the MUC5AC respiratory mucin in human bronchial epithelial cells, via PKC, EGF/TGF-alpha, Ras/Raf, MEK, ERK and Sp1-dependent mechanisms. J Mol Biol 344, 683–695.

Kim, Y.-J., Cho, H.-J., Shin, W.-C., Song, H.-A., Yoon, J.-H., and Kim, C.-H. (2014). Hypoxia-mediated mechanism of MUC5AC production in human nasal epithelia and its implication in rhinosinusitis. PLoS One 9, e98136.

Lee, Y.C., Oslund, K.L., Thai, P., Velichko, S., Fujisawa, T., Duong, T., Denison, M.S., and Wu, R. (2011). 2,3,7,8-Tetrachlorodibenzo-p-dioxin–Induced MUC5AC Expression. Am J Respir Cell Mol Biol 45, 270–276.

Perrais, M., Pigny, P., Copin, M., Aubert, J., and Van Seuningen, I. (2002). Induction of MUC2 and MUC5AC mucins by factors of the epidermal growth factor (EGF) family is mediated by EGF receptor/Ras/Raf/extracellular signal-regulated kinase cascade and Sp1. J Biol Chem 277, 32258–32267.

Van Seuningen, I., Pigny, P., Perrais, M., Porchet, N. and Aubert, J.P., 2001. Transcriptional regulation of the 11p15 mucin genes. Towards new biological tools in human therapy, in inflammatory diseases and cancer. Front Biosci 6, D1216-D1234.
 
Wan, H., Kaestner, K.H., Ang, S.L., Ikegami, M., Finkelman, F.D., Stahlman, M.T., Fulkerson, P.C., Rothenberg, M.E., and Whitsett, J.A. (2004). Foxa2 regulates alveolarization and goblet cell hyperplasia. Development 131, 953-964.
 

Wu, D.Y., Wu, R., Reddy, S.P., Lee, Y.C., and Chang, M.M.-J. (2007). Distinctive epidermal growth factor receptor/extracellular regulated kinase-independent and -dependent signaling pathways in the induction of airway mucin 5B and mucin 5AC expression by phorbol 12-myristate 13-acetate. Am J Pathol 170, 20–32.