Synergistic activity of STAT3 and c-Jun at a specific array of DNA elements in the alpha 2-macroglobulin promoter.
The transcriptional activity of natural promoters is sensitive to the precise spatial arrangement of DNA elements and their incorporation into higher order DNA-protein complexes. STAT3 and c-Jun form a specific ternary complex in vitro with a synthetic DNA element containing AP1 and SIE sites. These associations are critical for synergistic activation of transcription from a synthetic promoter by STAT3 and c-Jun. Expression of the acute phase protein alpha(2)-macroglobulin is induced in vivo by interleukin-6 (IL-6)-related cytokines; we demonstrate that coordinate interactions among STAT3, c-Jun, and a specific array of DNA elements contribute to activation of the alpha(2)-macroglobulin promoter in response to IL-6 family members. At least five promoter elements are involved in activation: two AP1 sites at -113 to -107 and -152 to -140, an acute phase response element (APRE (SIE)) at -171 to -163, and two AT-rich regions at -143 to -138 and -128 to -123. Synergism between STAT3 or STAT3-C and c-Jun is impaired by mutation of the APRE (SIE) or either AP1 site, as well as by mutations that alter the AT-rich regions or their phasing. Mutations of STAT3 previously shown to disrupt physical and functional interactions with c-Jun do not impair synergy between STAT3-C and c-Jun at the alpha(2)-macroglobulin promoter in HepG2 cells, suggesting that STAT3-C and STAT3 differ with respect to their precise contacts with c-Jun.
Yoo
J Y
JY
Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Wang
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Desiderio
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Nathans
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D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D016755:Proto-Oncogene Proteins c-jun; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D004247:DNA