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 repres ses the interleukin-6 signal transduction pathway that uses the same J AK tyrosine kinase and STAT (signal transducer and activator of transc ription) transcription factor as LIF. Here, we report that the LIF-JAK -STAT signal transduction pathway is blocked in cellular E1A-expressin g undifferentiated F9 cells, and that the block is overcome by retinoi c 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 remarka bly increased by LIF treatment in differentiated F9 (dF9) cells. We an alyzed the mechanism of the APRE regulation and found that the LIF-ind uced APRE-binding activity was regulated in a differentiation-dependen t manner. The protein levels and the tyrosine phosphorylation of JAK1, JAK2, and STAT3 in F9 cells were not different from those in dF9 cell s. The exogenous expression of activated c-Ha-ras partially recovered the LIF respon siveness of the APRE-luciferase gene in F9 cells, but t he dominant negative ras N-17 did not repress the LIF-induced activati on of APRE-luciferase in dF9 cells. These results suggested that an un known coactivation process that is partially compensated by Ras is req uired for STAT3-APRE binding in F9 cells.