Lack of a Role for Jun Kinase and AP-1 in Fas-Induced Apoptosis

Lenczowski, Joi M.; Domínguez, L.; Eder, Astrid; King, Leslie B.; Zacharchuk, Charles; Ashwell, Jonathan D.

doi:10.1128/mcb.17.1.170

Cited by 232 publications

(181 citation statements)

References 75 publications

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“…Fasand tumor necrosis factor-mediated apoptosis). 40,41 The mechanism by which JNK becomes activated in response to apoptotic signals is not completely understood. JNK activity is regulated by specific kinases (e.g.…”

Section: Discussionmentioning

confidence: 99%

ZBP-89-induced apoptosis is p53-independent and requires JNK

et al. 2004

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ZBP-89 induces apoptosis in human gastrointestinal cancer cells through a p53-independent mechanism. To understand the apoptotic pathway regulated by ZBP-89, we identified downstream signal transduction targets. Ectopic expression of ZBP-89 induced apoptosis through the mitochondrial pathway and was accompanied by activation of all three MAP kinase subfamilies: JNK1/2, ERK1/2 and p38 MAP kinase. ZBP-89-induced apoptosis was markedly enhanced by ERK inhibition with U0126. In contrast, inhibiting JNK with a JNK1-specific peptide inhibitor or dominant-negative JNK2 expression abrogated ZBP-89-mediated apoptosis. The p38 inhibitor SB202190 had no effect on ZBP-89-induced cell death. Protein dephosphorylation assays revealed that ZBP-89 activates JNK via repression of JNK dephosphorylation. Oligonucleotide microarray analyses revealed that ectopic expression of ZBP-89 downregulated expression of the dual-specificity phosphatase MKP6. Overexpression of MKP6 blocked ZBP-89-induced JNK phosphorylation and PARP cleavage. In addition, ectopic expression of ZBP-89 repressed Bcl-xL and Mcl-1 expression, but had no effect on Bcl-2. Silencing ZBP-89 with small interfering RNA enhanced both Bcl-xL and Mcl-1 expression. Taken together, ZBP-89-mediated apoptosis occurs via a p53-independent mechanism that requires JNK activation.

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Section: Discussionmentioning

confidence: 99%

ZBP-89-induced apoptosis is p53-independent and requires JNK

et al. 2004

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“…Also, Fas-induced apoptosis of Jurkat T cells was reported to be mediated by the JNK/p38 MAPK pathway downstream of Rac (Brenner et al, 1997). In contrast, the activation of JNK and p38 MAPK accompanied by Fas-mediated cell death was shown to occur downstream of caspases (Juo et al, 1997) and thus is not considered to be a critical event (Lenczowski et al, 1997;Nagata, 1997). Rather, the JNK pathway mediates survival signals in T cells (Nishina et al, 1997).…”

Section: Phosphorylation Of Threonine-308 and Serine-473 Is Critical mentioning

confidence: 99%

Anti-apoptotic function of Rac in hematopoietic cells

Nishida¹,

Kaziro²,

Satoh

1999

Oncogene

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The small GTP-binding protein Rac plays a pivotal role in the regulation of diverse physiological events including reorganization of the actin cytoskeleton, cell cycle progression, and transformation. Here we show an anti-apoptotic e ect of Rac in interleukin-3-dependent murine hematopoietic BaF3 cells. Activated Rac(G12V), when ectopically expressed in BaF3 cells, rendered the cells resistant to apoptosis upon interleukin-3 deprivation, while activated mutants of Rho and Cdc42 displayed no signi®cant anti-apoptotic e ect. In contrast to activated Ras, which also supports cell survival in the absence of interleukin-3, Rac required fetal bovine serum for the prevention of cell death. The involvement of phosphatidylinositol 3-kinase downstream of Rac was demonstrated by the inhibition of Rac-induced cell survival by wortmannin and LY294002 and the presence of phosphatidylinositol kinase activity in the Rac immunoprecipitate. Furthermore, the serine/threonine kinase Akt was stimulated by activated Rac and fetal bovine serum in a synergistic manner. Rac-induced Akt activation was mediated by phosphorylation of threonine-308 and serine-473. In addition to the phosphatidylinositol 3-kinase/Akt pathway, the p38 mitogen-activated protein kinase pathway was crucial for Rac-dependent survival, whereas p38 mitogen-activated protein kinase was not implicated in Ras-induced anti-apoptotic signaling. These ®ndings provide evidence for the involvement of Rac in survival signaling of hematopoietic cells.

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“…It has been shown that in many cases, apoptosis correlates with the stimulation of the stress activated MAP kinases SAPK/ JNK and p38 (reviewed in Schulze-Ostho et al, 1998), which are downstream targets of Cdc42Hs and Rac1 (Coso et al, 1995;Minden et al, 1994). However, numerous cases of apoptosis occurring independently of JNK activation have also been described (Khwaja and Lenczowski et al, 1997;Liu et al, 1996).…”

Section: Introductionmentioning

confidence: 99%