Cytokines that associate with the signal transducer gp130 activate the interferon-induced transcription factor p91 by tyrosine phosphorylation.
Interleukin-6, leukemia inhibitory factor, and oncostatin M exert a broad range of similar biological activities through association of their receptors with the signal-transducing component gp130. Although it is known that these cytokines trigger rapid tyrosine phosphorylation of a common set of cellular proteins as well as induction of several of the same early response genes, the mechanisms by which these genes are activated is not well understood. In this report, we show that interleukin-6, leukemia inhibitory factor, and oncostatin M stimulate the assembly of protein complexes that recognize conserved sequences within the enhancers of two genes (interferon regulatory factor 1 and Fc gamma receptor type I) that are rapidly activated by these cytokines. These enhancers are known to be required for transcriptional induction of these genes by interferon-gamma. Assembly of the DNA-binding protein complexes occurs within minutes after ligand addition and depends upon tyrosine phosphorylation. These complexes contain the p91 transcription factor, which is tyrosine-phosphorylated in response to these cytokines. An additional tyrosine-phosphorylated protein of 93 kDa can be coimmunoprecipitated with antibodies against p91. These findings further expand the network of cytokines known to activate p91 and, in addition, support the concept that sets of tyrosine-phosphorylated proteins may be responsible for the cytokine-regulated expression of early response genes.
Feldman
G M
GM
Division of Cytokine Biology, Food and Drug Administration, Bethesda, Maryland 20892.
Petricoin
E F
EF
David
M
M
Larner
A C
AC
Finbloom
D S
DS
D000818:Animals; D015703:Antigens, CD; D001483:Base Sequence; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D050856:Interferon Regulatory Factor-1; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D010750:Phosphoproteins / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D011961:Receptors, Fc / Q000235:genetics; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014443:Tyrosine / Q000378:metabolism*
D015703:Antigens, CD; D016207:Cytokines; D004268:DNA-Binding Proteins; C494200:Il6st protein, mouse; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D010750:Phosphoproteins; D011961:Receptors, Fc; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D050822:Cytokine Receptor gp130; D014443:Tyrosine