Interferon-stimulated response elements

All interferon-stimulated genes are characterized by the presence of an associated interferon-stimulated response element (ISRE). Signal transduction culminates in the binding of specific regulatory factors to the ISRE, which stimulates RNA polymerase Il-mediated transcription of the interferon-sensitive genes. The induced gene products then mediate the antiviral, immunomodulatory and other effects characteristically induced by interferons. 

The three activated STATs disengage from the receptor and bind to the cytoplasmic protein, p48. This entire complex translocates to the nucleus, where it interacts directly with upstream regulatory regions of IFN-sensitive genes. These nucleotide sequences are termed interferon-stimulated response elements (ISREs). This induces/augments expression of specific genes, as discussed later. 

Fig. 11.8. Scheme of signal transduction via interferon a. The receptor for interferon a (IFNa) binds and activates the Jak kinases Jakl and Tykl. These phosphorylate the Stat factors Statl and Stat2, leading to formation of Statl-Stat2 heterodimers. The heterodimers are transported into the nucleus and bind to a corresponding DNA element known as ISRE (interferon stimulated response element). Another protein, p48, is also involved in transcription activation of the interferon regulated gene. 

Fig. 10.5a). Differences in the length of spacers between TT and AA in the GAS-element are thought to be responsible for discrimination between different STAT transcription factors. Interferon-cc/p signals are transmitted through heterodimeric STAT 1/STAT 2, which form a complex with a protein, p48, and recruit ISGF3 (the interferon-stimulated gene factor 3), and address the interferon-stimulated response element (ISRE) (Fig. 10.5b). 

Matsuyama T, Grossman A, Mittrucker H-W, et al. Molecular cloning of LSIRF, a lymphoid-specific member of the interferon regulatory factor family that binds the interferon-stimulated response element (ISRE). Nucleic Acids Res. 1995 23 2127-2136. 

Takeda K, KamanakaM, TanakaT, Kishimoto T, Akira S. Impaired IL-13-mediated functions of macrophages in Stat6-deflcientmice. J Immunol 1996 157 3220-3222. Ohmori Y, Hamilton TA. The interferon-stimulated response element and a kappa B site mediate synergistic induction of murine IP-10 gene transcription by IFN-gamma and TNF-alpha. J Immunol 1995 154 5235-5244. 

Fig. 10.5 (a) Homodrmenc, phosphorylated STAT 1 and STAT 1/STAT 2 heterodimers bind in response to interferorr-yto the same DIMA sequence element, GAS. (b) Interferon-a/p activates the transcription factor complex containing p48/ISGF3 and STAT 1/STAT 2 heterodimers. This transcription-factor complex addresses the interferon-stimulated regulatory element, ISRE. 

S. J. Haque and B. R. Williams. Identification and characterization of an interferon (IFN)-stimulated response element-IFN-stimulated gene factor 3-independent signaling pathway for IFN-alpha. J Biol Chem. 269 (30), 19523-19529, 1994. 

Naschberger, E., Werner, T., Vicente, A. B., Guenzi, E., Topolt, K., Leubert, R., Lubeseder-Martellato, C., Nelson, P. J., and Sturzl, M. (2004). Nuclear factor-kappaB motif and interferon-alpha-stimulated response element co-operate in the activation of guanylate-binding protein-1 expression by inflammatory cytokines in endothelial cells. Biochem. J. 379, 409 20. 

Caldenhoven, E., Coffer, P., Yuan, J., Van De Stolpe, A., Horn, F., Kruijer, W. and Van Der Saag, P.T. (1994) Stimulation of the human intercellular adhesion molecule-1 promoter by interleukin-6 and interferon-y involves binding of distinct factors to a palindromic response element. / Biol. Chem. 269 21146-21154. 

---