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Stat3-dependent induction of BATF in M1 mouse myeloid leukemia cells
Takeshi Senga1, Takashi Iwamoto, Sean E Humphrey
1Department of Molecular Pathogenesis, Nagoya University School of Medicine, 65 Tsurumai Showa Nagoya 466-8550, Japan.
Abstract:
Stat3 mediates cellular responses associated with proliferation, survival and differentiation, but the mechanisms underlying the diverse effects of this signaling molecule remain unknown. M1 mouse myeloid leukemia cells arrest growth and differentiate into macrophages following treatment with interleukin 6 (IL-6) or leukemia inhibitory factor (LIF), and recent studies have shown that Stat3 plays a central role in this process. Utilizing representational difference analysis, we demonstrate that expression of the mouse BATF gene is upregulated as an early response to IL-6/LIF stimulation and Stat3 activation in this cell system. Immunoblots using antibodies to BATF detected an increase in BATF protein in response to LIF/IL-6 stimulation. BATF is a member of the AP-1 family of basic leucine zipper transcription factors and functions to inhibit the transcriptional and biological functions of AP-1 activity in mammalian cells. BATF forms complexes with c-Jun in M1 cells and forced expression of BATF in the absence of Stat3 signaling results in a reduced rate of cellular growth. These results indicate that Stat3 mediates cellular growth by modulating AP-1 activity through the induction of BATF.
Insights
Signal transducer and activator of transcription 3 (Stat3) regulates cell growth by inducing the transcription factor BATF (basic leucine zipper ATF-like transcription repressor). This modulation of AP-1 activity is key to Stat3
Area of Science:
- Molecular Biology
- Cell Signaling
- Cancer Research
Background:
- Signal transducer and activator of transcription 3 (Stat3) is crucial for cell proliferation, survival, and differentiation.
- The precise mechanisms by which Stat3 exerts its diverse cellular effects are not fully understood.
- Stat3 plays a central role in the growth arrest and differentiation of M1 mouse myeloid leukemia cells into macrophages upon stimulation with IL-6 or LIF.
Purpose of the Study:
- To elucidate the molecular mechanisms through which Stat3 mediates cellular responses, particularly in the context of M1 cell differentiation.
- To identify early gene expression changes induced by Stat3 activation in response to IL-6/LIF.
- To investigate the role of the transcription factor BATF in Stat3-mediated cellular processes.
Main Methods:
- Representational difference analysis (RDA) to identify differentially expressed genes.
- Western blotting (immunoblotting) to detect protein expression levels.
- Cell culture experiments involving M1 mouse myeloid leukemia cells stimulated with IL-6 or LIF.
- Analysis of transcription factor complex formation (BATF with c-Jun).
Main Results:
- Expression of the mouse BATF gene was significantly upregulated as an early response to IL-6/LIF stimulation and Stat3 activation in M1 cells.
- Increased BATF protein levels were confirmed by immunoblotting following LIF/IL-6 stimulation.
- BATF, a member of the AP-1 family, forms complexes with c-Jun and inhibits AP-1 activity.
- Forced expression of BATF in the absence of Stat3 signaling led to a reduced rate of cellular growth.
Conclusions:
- Stat3 mediates cellular growth regulation by inducing the expression of the transcription factor BATF.
- The induction of BATF by Stat3 leads to the modulation of AP-1 activity, impacting cellular proliferation.
- These findings reveal a novel mechanism by which Stat3 controls cell growth and differentiation through the BATF-AP-1 pathway.