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STAT3 orchestrates contradictory signals in cytokine-induced G1 to S cell-cycle transition
T Fukada1, T Ohtani, Y Yoshida
1Division of Molecular Oncology, Biomedical Research Center, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Abstract:
The signal transducer and activator of transcription molecules (STATs) play key roles in cytokine-induced signal transduction. However, their role in cell growth has not been clear. In the present study, we show that STAT3 plays a key role in the G1 to S phase cell-cycle transition induced by the cytokine receptor subunit gp130, through the upregulation of cyclins D2, D3 and A, and cdc25A, and the concomitant downregulation of p21 and p27. Furthermore, unexpectedly, we found that gp130 could induce the expression of p21 when STAT3 activation was suppressed. Such contradictory signals regulating cell-cycle progression could be simultaneously delivered from distinct cytoplasmic regions of gp130. We propose an 'orchestrating model' for cytokine and growth factor action in which contradictory signals are orchestrated to produce a specific effect in a target cell.
Insights
Signal transducer and activator of transcription 3 (STAT3) drives cell cycle progression via cytokine signaling. Unexpectedly, gp130 also induces cell cycle inhibitors when STAT3 is suppressed, revealing complex signaling.
Area of Science:
- Cell Biology
- Molecular Biology
- Signal Transduction
Background:
- Signal transducer and activator of transcription (STAT) molecules are crucial for cytokine signaling.
- The precise role of STATs in regulating cell growth and the cell cycle remains incompletely understood.
Purpose of the Study:
- To elucidate the role of STAT3 in cytokine-induced cell cycle progression mediated by gp130.
- To investigate the mechanisms by which gp130 signaling influences cell cycle regulators.
Main Methods:
- Investigated the role of STAT3 in the G1 to S phase cell cycle transition.
- Analyzed the expression of cyclins (D2, D3, A), cdc25A, p21, and p27.
- Examined the effect of STAT3 suppression on gp130-induced signaling.
Main Results:
- STAT3 activation by gp130 upregulates cyclins D2, D3, A, and cdc25A, promoting cell cycle progression.
- STAT3 activation leads to the downregulation of cell cycle inhibitors p21 and p27.
- gp130 induced p21 expression even when STAT3 activation was inhibited, indicating parallel signaling pathways.
Conclusions:
- STAT3 is a key mediator of gp130-induced cell cycle progression.
- Distinct cytoplasmic regions of gp130 can deliver contradictory signals simultaneously.
- Proposed an 'orchestrating model' where cells integrate opposing signals for specific cellular outcomes.