Mammary gland factor activated by prolactin on mammary epithelial cells and acute-phase response factor activated by interleukin-6 in liver cells share DNA binding and transactivation potential.
We have studied transcription factors that are coupled to the activation of cytokine receptors in liver and in mammary epithelial cells. Interleukin-6 (IL-6) causes the rapid activation of the acute-phase response factor (APRF) in the liver of animals during acute inflammation and in cultured human hepatoma cells (HepG2) and induces the transcription of the acute-phase protein genes, e.g. alpha 2-macroglobulin (alpha 2-M). In the mammary gland and in cultured HC11 mammary epithelial cells, milk protein genes, e.g. beta-casein, are induced by the lactogenic hormones, insulin, glucocorticoids, and PRL. The induction of the beta-casein gene promoter is preceded by the activation of the mammary gland factor (MGF). We have compared the DNA binding sequences of APRF and MGF, 5'-CTTCTT/GGGAATT-3', and have found that they coincide in 11 of 12 positions. Bandshift experiments and oligonucleotide competition experiments showed that both factors, MGF and APRF, are able to bind to the IL-6 response element of the alpha 2-M gene promoter and to the lactogenic hormone response element of the beta-casein gene promoter with very similar specificities. Partial proteolytic digestion of APRF and MGF DNA complexes yielded similar clipping patterns. The UV cross-linked DNA complexes of both transcription factors were of the same apparent molecular mass. IL-6 activation of APRF in HepG2 cells can be observed within minutes. MGF induction by PRL in HC11 cells occurs with similar kinetics. The synergistic action of glucocorticoids and PRL is necessary for the induction of the beta-casein gene, but PRL is sufficient for MGF activation.(ABSTRACT TRUNCATED AT 250 WORDS)
Standke
G J
GJ
Friedrich Miescher-Institute, Basel, Switzerland.
Meier
V S
VS
Groner
B
B
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002364:Caseins / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D016384:Consensus Sequence; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004847:Epithelial Cells; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology; D008321:Mammary Glands, Animal / Q000166:cytology; D051379:Mice; D008894:Milk Proteins; D008969:Molecular Sequence Data; D009928:Organ Specificity; D011388:Prolactin / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D051381:Rats; D018123:Receptors, Interleukin / Q000187:drug effects* / Q000502:physiology; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D000511:alpha-Macroglobulins / Q000096:biosynthesis / Q000235:genetics
D002364:Caseins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D008894:Milk Proteins; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; C494093:Stat5a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000511:alpha-Macroglobulins; D011388:Prolactin; D004247:DNA