Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|EGFR Activation Leading to Decreased Lung Function||KE||Moderate|
Level of Biological Organization
How this Key Event works
SP1 is a member of the zinc finger transcription factors which are involved in many biological processes including cell cycle, apoptosis, angiogenesis, hormonal activation. SP1 can be phosphorylated by many kinases including PKA, PKC-zeta, ERK and CDK, as well as in response to viral infection. Growth factors such as EGF and FGF2 can phosphorylate SP1 through ERK, and HGF can activate the VEGF promoter through PI3K, MEK and PKC-zeta. There are five confirmed phosphorylation sites on Sp1: Ser59, Ser131, Thr453, Thr579, and Thr739 which can result in both positive and negative effects on SP1 DNA binding and activation of the target promoter (Chu and Ferro, 2005).
SP1 induces MUC5AC expression in the lung through EGFR/MAPK activation in a mouse lung influenza model (Barbier et al., 2012).
How it is Measured or Detected
Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?
SP1 activity is detected by phosphorylated SP1 via immunoblotting. SP1 activity is inhibited with mithramycin C.
SP1 binding is studied using electrophoretic mobility shift assay (EMSA) and site-directed mutagenesis (for MUC5AC −192 promoter construct).
Evidence Supporting Taxonomic Applicability
SP1 activation has been reported in mouse, human and rat literature and is orthologous between these species.
1. 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.
2. Chu, S., and Ferro, T.J. (2005). Sp1: Regulation of gene expression by phosphorylation. Gene 348, 1–11.