Signaling pathways to the assembly of an interferon-beta enhanceosome. Chemical genetic studies with a small molecule.
Small molecules that modulate specific protein functions are valuable tools for dissecting complex signaling pathways. Here, we identified a small molecule that induces the assembly of the interferon-beta (IFN-beta) enhanceosome by stimulating all the enhancer-binding activator proteins: ATF2/c-JUN, IRF3, and p50/p65 of NF-kappaB. This compound stimulates mitogen-activated protein kinase kinase kinase 1 (MEKK1), which is a member of a family of proteins involved in stress-mediated signaling pathways. Consistent with this, MEKK1 activates IRF3 in addition to ATF2/c-JUN and NF-kappaB for the assembly of the IFN-beta enhanceosome. MEKK1 activates IRF3 through the c-JUN amino-terminal kinase (JNK) pathway but not the p38 and IkappaB kinase (IKK) pathway. Taken together with previous observations, these results implicate that, for the assembly of an IFN-beta enhanceosome, MEKK1 can induce IRF3 and ATF2/c-JUN through the JNK pathway, whereas it can induce NF-kappaB through the IKK pathway. Thus, specific MEKK family proteins may be able to integrate some of multiple signal transduction pathways leading to the specific activation of the IFN-beta enhanceosome.
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National Creative Research Initiative Center for Genetic Reprogramming, Institute for Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Korea. tk_kim@hms.harvard.edu
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D004742:Enhancer Elements, Genetic; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
D014157:Transcription Factors; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human