Alternative signaling mechanism of leukemia inhibitory factor responsiveness in a differentiating embryonal carcinoma cell.
Leukemia inhibitory factor (LIF) is a cytokine that plays an important role during mouse embryogenesis. We showed that adenovirus E1A represses the interleukin-6 signal transduction pathway that uses the same JAK tyrosine kinase and STAT (signal transducer and activator of transcription) transcription factor as LIF. Here, we report that the LIF-JAK-STAT signal transduction pathway is blocked in cellular E1A-expressing undifferentiated F9 cells, and that the block is overcome by retinoic acid-induced differentiation. LIF failed to stimulate the expression of the acute phase response element (APRE)-driven luciferase gene in undifferentiated F9 cells, whereas the luciferase activity was remarkably increased by LIF treatment in differentiated F9 (dF9) cells. We analyzed the mechanism of the APRE regulation and found that the LIF-induced APRE-binding activity was regulated in a differentiation-dependent manner. The protein levels and the tyrosine phosphorylation of JAK1, JAK2, and STAT3 in F9 cells were not different from those in dF9 cells. The exogenous expression of activated c-Ha-ras partially recovered the LIF responsiveness of the APRE-luciferase gene in F9 cells, but the dominant negative ras N-17 did not repress the LIF-induced activation of APRE-luciferase in dF9 cells. These results suggested that an unknown coactivation process that is partially compensated by Ras is required for STAT3-APRE binding in F9 cells.
Takeda
T
T
Department of Obstetrics and Gynecology, Osaka University Medical School, Suita, Japan.
Kurachi
H
H
Yamamoto
T
T
Homma
H
H
Adachi
K
K
Morishige
K
K
Miyake
A
A
Murata
Y
Y
D000209:Acute-Phase Proteins / Q000235:genetics; D000818:Animals; D018236:Carcinoma, Embryonal / Q000473:pathology*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D011905:Genes, ras; D006131:Growth Inhibitors / Q000494:pharmacology*; D015850:Interleukin-6; D053613:Janus Kinase 1; D007700:Kinetics; D053605:Leukemia Inhibitory Factor; D008156:Luciferases / Q000235:genetics; D008222:Lymphokines / Q000494:pharmacology*; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D008156:Luciferases; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1