The LIF response element of the alpha 2 macroglobulin gene confers LIF-induced transcriptional activation in embryonal stem cells.
Leukaemia Inhibitory Factor (LIF), an interleukin 6 (IL-6)-type cytokine, is an essential growth factor for murine embryonal stem cells. The LIF-receptor was known in these cells, but the cell-internal part of the signal cascade and the transcription factors through which LIF controls its growth-promoting target genes in embryonal stem cells, had not been identified. This study shows that the type II IL-6-response element of the rat alpha 2 macroglobulin (alpha 2M) gene, which mediates IL-6- and LIF-responses in hepatic cells, also functioned as a LIF-response element (LIF-RE) in ES1 embryonal stem cells and P19 embryonal carcinoma cells. It conferred transcriptional activation by LIF of transfected reporter constructs in these cells. A characteristic DNA-binding activity interacting with this LIF-RE was induced by treatment of these cells with LIF. The complex between this activity and the LIF-RE had identical electrophoretic mobility, sequence-specificity and kinetics of induction as the complex with the corresponding LIF-response factor (LIF-RF) from hepatic cells. The transcription factor STAT3 was part of this complex, as shown by its reactivity with anti-STAT3 antibodies. Withdrawal of LIF from ES1 cells caused the induction of differentiation and the disappearance of this DNA-binding activity. Simultaneously, the surface density of high-affinity LIF receptors was reduced approximately 10-fold.
Hocke
G M
GM
Institute for Microbiology, Biochemistry & Genetics, University of Erlangen-Nürnberg, Germany.
Cui
M Z
MZ
Fey
G H
GH
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D054278:Embryonal Carcinoma Stem Cells; D006131:Growth Inhibitors / Q000235:genetics* / Q000494:pharmacology; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000235:genetics* / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D000511:alpha-Macroglobulins / Q000235:genetics*
D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D000511:alpha-Macroglobulins