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Association of Stat3-dependent transcriptional activation of p19INK4D with IL-6-induced growth arrest
M Narimatsu1, K Nakajima, M Ichiba
1Department of Oncology, Biomedical Research Center, Osaka University Medical School, Suita, Japan.
Abstract:
Signal transducer and activator of transcription 3 (Stat3) is the major mediator of the IL-6-induced signals regulating growth and differentiation. In the M1 myeloleukemic cell line, Stat3 is a critical transcription factor causing repression of c-myc and c-myb genes, expression of junB and IRF1, growth arrest at G1, and subsequent macrophage differentiation. To understand the mechanisms by which Stat3 causes such effects, we searched for other Stat3-regulated genes possibly involved in growth arrest. We identified this inducible molecule as p19INK4D using a specific antibody. Both p19INK4D mRNA and protein were rapidly induced by IL-6 treatment without requiring de novo protein synthesis and the induction was fully suppressed by dominant-negative forms of Stat3. Thus both Stat3-regulated events, repressions of c-myc and c-myb and induction of p19INK4D, are likely to be involved in IL-6-induced growth arrest in M1 cells.
Insights
Signal transducer and activator of transcription 3 (Stat3) mediates IL-6 signals. In M1 cells, Stat3 induces p19INK4D, contributing to growth arrest and macrophage differentiation.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Signal transducer and activator of transcription 3 (Stat3) is a key mediator of interleukin-6 (IL-6) signaling pathways.
- In M1 myeloleukemic cells, Stat3 regulates genes involved in growth, differentiation, and cell cycle arrest.
Purpose of the Study:
- To identify novel Stat3-regulated genes involved in IL-6-induced growth arrest in M1 cells.
- To elucidate the role of these genes in the differentiation process.
Main Methods:
- Utilized specific antibodies to identify Stat3-regulated proteins.
- Analyzed gene and protein expression levels following IL-6 treatment.
- Employed dominant-negative Stat3 forms to confirm Stat3-dependent regulation.
Main Results:
- Identified p19INK4D as an IL-6-inducible gene regulated by Stat3.
- Demonstrated rapid induction of p19INK4D mRNA and protein upon IL-6 stimulation, independent of new protein synthesis.
- Confirmed that Stat3 activation is essential for p19INK4D induction.
Conclusions:
- Stat3-mediated induction of p19INK4D is a critical event in IL-6-induced growth arrest in M1 myeloleukemic cells.
- The repression of c-myc and c-myb, along with p19INK4D induction, collectively contribute to the observed growth arrest and differentiation phenotype.