Functional involvement of Daxx in gp130-mediated cell growth and survival in BaF3 cells.
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.
Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku, Sapporo, Japan.
Ryuta
R
Muromoto
Makoto
M
Kuroda
Sumihito
S
Togi
Yuichi
Y
Sekine
Asuka
A
Nanbo
Kazuya
K
Shimoda
Kenji
K
Oritani
Tadashi
T
Matsuda
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D056970:Co-Repressor Proteins; D050822:Cytokine Receptor gp130 / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C491473:Daxx protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C052617:Bcl2 protein, mouse; D050822:Cytokine Receptor gp130; D007770:L-Lactate Dehydrogenase