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Functional involvement of Daxx in gp130-mediated cell growth and survival in BaF3 cells
Ryuta Muromoto1, Makoto Kuroda, Sumihito Togi
1Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku, Sapporo, Japan.
Abstract:
Death domain-associated protein (Daxx) is a multifunctional protein that modulates both cell death and transcription. Several recent studies have indicated that Daxx is a mediator of lymphocyte death and/or growth suppression, although the detailed mechanism is unclear. Previously, we reported that Daxx suppresses IL-6 family cytokine-induced gene expression by interacting with STAT3. STAT3 is important for the growth and survival of lymphocytes; therefore, we here examined the role of Daxx in the gp130/STAT3-dependent cell growth/survival signals. We found that Daxx suppresses the gp130/STAT3-dependent cell growth and that Daxx endogenously interacts with STAT3 and inhibits the DNA-binding activity of STAT3. Moreover, small-interfering RNA-mediated knockdown of Daxx enhanced the expression of STAT3-target genes and accelerated the STAT3-mediated cell cycle progression. In addition, knockdown of Daxx-attenuated lactate dehydrogenase leakage from cells, indicating that Daxx positively regulates cell death during gp130/STAT3-mediated cell proliferation. Notably, Daxx specifically suppressed the levels of Bcl2 mRNA and protein, even in cytokine-unstimulated cells, indicating that Daxx regulates Bcl2 expression independently of activated STAT3. These results suggest that Daxx suppresses gp130-mediated cell growth and survival by two independent mechanisms: inhibition of STAT3-induced transcription and down-regulation of Bcl2 expression.
Insights
Death domain-associated protein (Daxx) suppresses lymphocyte growth by inhibiting STAT3 and down-regulating Bcl2. This dual action promotes cell death, revealing Daxx
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Death domain-associated protein (Daxx) is a multifunctional protein involved in cell death and transcription.
- Daxx has been implicated in lymphocyte death and growth suppression, but the precise mechanisms remain unclear.
- STAT3 is crucial for lymphocyte growth and survival, and Daxx was previously shown to interact with STAT3, suppressing IL-6 family cytokine-induced gene expression.
Purpose of the Study:
- To investigate the role of Daxx in gp130/STAT3-dependent cell growth and survival signals in lymphocytes.
- To elucidate the molecular mechanisms by which Daxx regulates lymphocyte proliferation and death.
Main Methods:
- Small-interfering RNA (siRNA)-mediated knockdown of Daxx.
- Analysis of STAT3 DNA-binding activity.
- Measurement of STAT3-target gene expression.
- Assessment of cell cycle progression.
- Quantification of lactate dehydrogenase leakage.
- Evaluation of Bcl2 mRNA and protein levels.
Main Results:
- Daxx suppresses gp130/STAT3-dependent lymphocyte growth and survival.
- Daxx interacts with STAT3, inhibiting its DNA-binding activity and subsequent transcription of target genes.
- Daxx knockdown enhances STAT3-mediated cell cycle progression and reduces cell death.
- Daxx down-regulates Bcl2 expression independently of STAT3 activation.
Conclusions:
- Daxx suppresses gp130-mediated lymphocyte growth and survival through two distinct pathways.
- Daxx inhibits STAT3-induced transcription and also down-regulates Bcl2 expression.
- These findings highlight Daxx as a key regulator of lymphocyte homeostasis, impacting both proliferation and cell death pathways.
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