TY - JOUR
T1 - Requirement of c-Jun NH2-terminal kinase activation in interferon-α-induced apoptosis through upregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in Daudi B lymphoma cells
AU - Yanase, Noriko
AU - Hata, Kikumi
AU - Shimo, Kuniaki
AU - Hayashida, Miho
AU - Evers, B. Mark
AU - Mizuguchi, Junichiro
PY - 2005/10/15
Y1 - 2005/10/15
N2 - Interferon α (IFN-α) inhibits growth, at least in part, through induction of apoptosis. However, the molecular mechanisms underlying IFN-α-induced apoptosis are not completely understood. In the present study, we found that IFN-α induced a sustained activation of c-Jun N-terminal kinase 1 (JNK1), but not extracellular kinases (ERKs), in Daudi B lymphoma cells, as assessed by Western blotting using phospho-specific antibodies. Several lines of evidence support the notion that the IFN-α-induced activation of JNK is responsible for IFN-α-induced apoptosis, at least in part, through upregulation of TNF-related apoptosis-inducing ligand (TRAIL). First, pretreatment of Daudi cells with a JNK inhibitor reduced IFN-α-induced upregulation of TRAIL and loss of mitochondrial membrane potential (ΔΨm) and annexin-positive cells, which was assessed by flow cytometry. Second, a dominant-negative form of JNK1 (dnJNK1) also reduced these apoptotic events, while a constitutively active form of JNK1, MKK7-JNK1β, enhanced them. Finally, treatment with IFN-α enhanced the promoter activity of the TRAIL gene, which was partially abrogated by either JNK inhibitor or dnJNK1, while it was moderately enhanced by MKK7-JNK1β. These findings are useful for understanding molecular mechanisms of IFN-α-induced apoptosis and also for development of treatment modalities of some tumors with IFN-α.
AB - Interferon α (IFN-α) inhibits growth, at least in part, through induction of apoptosis. However, the molecular mechanisms underlying IFN-α-induced apoptosis are not completely understood. In the present study, we found that IFN-α induced a sustained activation of c-Jun N-terminal kinase 1 (JNK1), but not extracellular kinases (ERKs), in Daudi B lymphoma cells, as assessed by Western blotting using phospho-specific antibodies. Several lines of evidence support the notion that the IFN-α-induced activation of JNK is responsible for IFN-α-induced apoptosis, at least in part, through upregulation of TNF-related apoptosis-inducing ligand (TRAIL). First, pretreatment of Daudi cells with a JNK inhibitor reduced IFN-α-induced upregulation of TRAIL and loss of mitochondrial membrane potential (ΔΨm) and annexin-positive cells, which was assessed by flow cytometry. Second, a dominant-negative form of JNK1 (dnJNK1) also reduced these apoptotic events, while a constitutively active form of JNK1, MKK7-JNK1β, enhanced them. Finally, treatment with IFN-α enhanced the promoter activity of the TRAIL gene, which was partially abrogated by either JNK inhibitor or dnJNK1, while it was moderately enhanced by MKK7-JNK1β. These findings are useful for understanding molecular mechanisms of IFN-α-induced apoptosis and also for development of treatment modalities of some tumors with IFN-α.
KW - Apoptosis
KW - B lymphocytes
KW - Human
KW - Interferon-α
KW - Mitochondria
KW - TRAIL
KW - c-Jun NH2-Terminal Kinase
UR - http://www.scopus.com/inward/record.url?scp=25844527193&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=25844527193&partnerID=8YFLogxK
U2 - 10.1016/j.yexcr.2005.06.021
DO - 10.1016/j.yexcr.2005.06.021
M3 - Article
C2 - 16099454
AN - SCOPUS:25844527193
SN - 0014-4827
VL - 310
SP - 10
EP - 21
JO - Experimental Cell Research
JF - Experimental Cell Research
IS - 1
ER -