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Alternative signaling mechanism of leukemia inhibitory factor responsiveness in a differentiating embryonal carcinoma

T Takeda1, H Kurachi, T Yamamoto

  • 1Department of Obstetrics and Gynecology, Osaka University Medical School, Suita, Japan.

Endocrinology
|July 1, 1997
PubMed

Insights

Leukemia inhibitory factor (LIF) signaling is blocked in undifferentiated F9 cells but restored upon differentiation. This suggests a differentiation-dependent coactivation process is crucial for LIF-induced gene expression.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Background:

  • Leukemia inhibitory factor (LIF) is a critical cytokine for mouse embryogenesis.
  • Adenovirus E1A protein interferes with the interleukin-6 (IL-6) signaling pathway, which shares components with the LIF pathway.
  • The LIF-JAK-STAT pathway involves Janus kinases (JAK) and signal transducers and activators of transcription (STAT) transcription factors.

Purpose of the Study:

  • To investigate the mechanism by which the LIF-JAK-STAT signal transduction pathway is blocked in undifferentiated F9 cells.
  • To determine if cellular differentiation overcomes this block.
  • To elucidate the role of differentiation in regulating the binding activity of STAT transcription factors.

Main Methods:

  • Utilized F9 embryonal carcinoma cells, both undifferentiated and retinoic acid-induced differentiated (dF9).
  • Assessed LIF-induced gene expression using an acute phase response element (APRE)-driven luciferase reporter assay.
  • Analyzed protein levels and tyrosine phosphorylation of JAK1, JAK2, and STAT3.
  • Investigated the role of Ras signaling by introducing activated c-Ha-ras or dominant-negative ras N-17.

Main Results:

  • The LIF-JAK-STAT pathway was blocked in undifferentiated F9 cells, as evidenced by the lack of LIF-induced APRE-luciferase activity.
  • LIF stimulation significantly increased APRE-luciferase activity in differentiated F9 (dF9) cells, indicating differentiation-dependent pathway activation.
  • STAT3 protein levels and tyrosine phosphorylation were similar in F9 and dF9 cells, suggesting the block is not due to these factors.
  • Exogenous expression of activated Ras partially restored LIF responsiveness in F9 cells, while dominant-negative Ras did not inhibit activation in dF9 cells.

Conclusions:

  • The LIF-JAK-STAT signaling pathway's function in F9 cells is dependent on the differentiation state.
  • A differentiation-dependent coactivation process, partially compensated by Ras, is essential for STAT3 binding to the APRE in undifferentiated F9 cells.
  • This study highlights the complex regulation of cytokine signaling during cellular differentiation.

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