Key Event Title
|Level of Biological Organization|
Key Event Components
|phosphorylation||transcription factor Sp1||increased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Decreased lung function||KeyEvent|
Key Event Description
Sp1 is a member of the zinc finger transcription factors which are involved in many biological processes including cell cycle, cell differentiation, cell growth, apoptosis, immune responses, response to DNA damage, and chromatin remodeling. Sp1 can be phosphorylated by many kinases including PKA, PKC-zeta, ERK and CDK. Growth factors such as EGF and FGF2 can phosphorylate Sp1 through ERK, and HGF can activate Sp1 through PI3K, MEK and PKC-zeta (reviewed by Tan and Khachigian, 2009). There are five confirmed phosphorylation sites on Sp1: Ser59, Ser131, Thr453, Thr579, and Thr739, and phosphorylation can result in both positive and negative effects on Sp1 DNA binding and activation of the target promoter (Chu and Ferro, 2005).
How It Is Measured or Detected
Activation of Sp1 can be confirmed by detecting phosphorylation at the known sites (Ser59, Ser131, Thr453, Thr579, and Thr739) using Western blots with phospho-specific antibodies. Confirmatory evidence for the involvement of Sp1 in MUC5AC transcription comes from electrophoretic mobility shift assay (EMSA) and site-directed mutagenesis experiments (Hewson et al., 2004). Specificity can be proven by inhibiting Sp1 with mithramycin C. This describes a very experimental approach; none of these methods is validated.
Domain of Applicability
Sp1 activation has been reported in mouse, rat and human, and Sp1 is orthologous between these species.
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.
Chu, S., and Ferro, T.J. (2005). Sp1: Regulation of gene expression by phosphorylation. Gene 348, 1–11.
Hewson, C.A., Edbrooke, M.R., and Johnston, S.L. (2004). PMA induces the MUC5AC respiratory mucin in human bronchial epithelial cells, via PKC, EGF/TGF-α, Ras/Raf, MEK, ERK and Sp1-dependent mechanisms. J Mol Biol 344, 683-695.
Perrais, M., Pigny, P., Copin, M.C., Aubert, J.P., 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.