Modulated kinase activities in cells undergoing tumour necrosis factor-induced apoptotic cell death (original) (raw)
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Journal of Biological Chemistry, 1998
Fas ligand and tumor necrosis factor ␣ (TNF) bind to members of the TNF receptor superfamily. Stimulation by Fas ligand results in apoptosis, whereas TNF induces multiple effects including proliferation, differentiation, and apoptosis. Activation of the c-Jun N-terminal kinase (JNK) and p38 kinase pathways is common to Fas and TNF signaling; however, their role in apoptosis is controversial. Fas receptor cross-linking induces apoptosis in the absence of actinomycin D and activates JNK in a caspase-dependent manner. In contrast, TNF requires actinomycin D for apoptosis and activates JNK and p38 kinase with biphasic kinetics. The first phase is transient, precedes apoptosis, and is caspase-independent, whereas the second phase is coincident with apoptosis and is caspase-dependent. Inhibition of early TNF-induced JNK and p38 kinases using MKK4/MKK6 mutants or the p38 inhibitor SB203580 increases TNF-induced apoptosis, whereas expression of wild type MKK4/MKK6 enhances survival. In contrast, the Mek inhibitor PD098059 has no effect on survival. These results demonstrate that early activation of p38 kinase (but not Mek) are necessary to protect cells from TNF-mediated cytotoxicity. Thus, early stress kinase activation initiated by TNF plays a key role in regulating apoptosis. Fas ligand (FasL) 1 and tumor necrosis factor ␣ (TNF) bind to members of the TNF receptor superfamily (1). Fas/CD95/ APO-1 receptor oligomerization induced by FasL or by agonist antibodies results in apoptosis in a variety of cells, including T, B, and NK cells, macrophages, and fibroblasts (2). TNF binds to two ubiquitously expressed receptors, TNF receptor I (TNFRI/ p55) and TNF receptor II (TNFRII/p75), that do not share any homology within their cytoplasmic domains (3). Unlike FasL, TNF elicits a wide range of cellular effects, including apoptosis, proliferation, differentiation, inflammation, and chemotaxis (4). FasL and TNF activate apoptotic signaling pathways through a similar mechanism. Fas and TNF interact either directly or indirectly with the adapter protein FADD/MORT1, which recruits caspase 8 to the receptor complex (reviewed in Ref. 3). The resulting cascade of caspase activation causes cleavage of cytosolic, cytoskeletal, and nuclear proteins and
Journal of Biological Chemistry, 1998
Fas ligand and tumor necrosis factor ␣ (TNF) bind to members of the TNF receptor superfamily. Stimulation by Fas ligand results in apoptosis, whereas TNF induces multiple effects including proliferation, differentiation, and apoptosis. Activation of the c-Jun N-terminal kinase (JNK) and p38 kinase pathways is common to Fas and TNF signaling; however, their role in apoptosis is controversial. Fas receptor cross-linking induces apoptosis in the absence of actinomycin D and activates JNK in a caspase-dependent manner. In contrast, TNF requires actinomycin D for apoptosis and activates JNK and p38 kinase with biphasic kinetics. The first phase is transient, precedes apoptosis, and is caspase-independent, whereas the second phase is coincident with apoptosis and is caspase-dependent. Inhibition of early TNF-induced JNK and p38 kinases using MKK4/MKK6 mutants or the p38 inhibitor SB203580 increases TNF-induced apoptosis, whereas expression of wild type MKK4/MKK6 enhances survival. In contrast, the Mek inhibitor PD098059 has no effect on survival. These results demonstrate that early activation of p38 kinase (but not Mek) are necessary to protect cells from TNF-mediated cytotoxicity. Thus, early stress kinase activation initiated by TNF plays a key role in regulating apoptosis. Fas ligand (FasL) 1 and tumor necrosis factor ␣ (TNF) bind to members of the TNF receptor superfamily (1). Fas/CD95/ APO-1 receptor oligomerization induced by FasL or by agonist antibodies results in apoptosis in a variety of cells, including T, B, and NK cells, macrophages, and fibroblasts (2). TNF binds to two ubiquitously expressed receptors, TNF receptor I (TNFRI/ p55) and TNF receptor II (TNFRII/p75), that do not share any homology within their cytoplasmic domains (3). Unlike FasL, TNF elicits a wide range of cellular effects, including apoptosis, proliferation, differentiation, inflammation, and chemotaxis (4). FasL and TNF activate apoptotic signaling pathways through a similar mechanism. Fas and TNF interact either directly or indirectly with the adapter protein FADD/MORT1, which recruits caspase 8 to the receptor complex (reviewed in Ref. 3). The resulting cascade of caspase activation causes cleavage of cytosolic, cytoskeletal, and nuclear proteins and
Molecular and Cellular Biology, 2002
The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) regulates immune responses, inflammation, and programmed cell death (apoptosis). TNF-α exerts its biological activities by activating multiple signaling pathways, including IκB kinase (IKK), c-Jun N-terminal protein kinase (JNK), and caspases. IKK activation inhibits apoptosis through the transcription factor NF-κB, whose target genes include those that encode inhibitors of both caspases and JNK. Despite activation of the antiapoptotic IKK/NF-κB pathway, TNF-α is able to induce apoptosis in cells sensitive to it, such as human breast carcinoma MCF-7 and mouse fibroblast LM cells. The molecular mechanism underlying TNF-α-induced apoptosis is incompletely understood. Here we report that in TNF-α-sensitive cells activation of the IKK/NF-κB pathway fails to block TNF-α-induced apoptosis, although its inactivation still promotes TNF-α-induced apoptosis. Interestingly, TNF-α-induced apoptosis is suppressed by inhibition of t...
Biochemical …, 2002
The activation of the extracellular signal-regulated kinases (ERKs) by tumour necrosis factor-α (TNF) receptors (TNFRs) is an integral part of the cytokine's pleiotropic cellular responses. Here we report differences in the caspase sensitivity and TNFR subtype activation of members of the ERK family. Inhibition in HeLa cells of caspase function by pharmacological inhibitors or the expression of CrmA (cytokine response modifier A), a viral modifier protein, blocks TNF-induced apoptosis or caspasedependent protein kinase Cδ and poly(ADP-ribose) polymerase protein degradation. TNFR1-or TNFR2-stimulated c-Jun N-terminal kinase (JNK) activity was attenuated in cells in which caspase activity was inhibited either by pharmacological blockers or CrmA expression. Both TNFR1-and TNFR2stimulated JNK activity was caspase-sensitive ; however, only TNFR1 was capable of stimulating p42\44 mitogen-activated
FEBS Letters, 1998
In the mouse fibrosarcoma cell line L929sA, tumor necrosis factor (TNF) stimulates activation of the stressresponsive p38 mitogen-activated protein kinase (MAPK), as well as the classical p42 and p44 MAPK. TNF signaling can be mediated by p55 or p75 TNF receptors. Here, we demonstrate that TNF-R55 is sufficient to activate p42/p44 MAPK and p38 MAPK. Moreover, by expressing different membrane-bound or purely cytoplasmic truncations of TNF-R55, we show that the intracellular death domain of TNF-R55 is the crucial domain involved. The cytoplasmic membrane-proximal region of TNF-R55, known to induce neutral sphingomyelinase activation, is not required for activation of p38 MAPK or p42/p44 MAPK.
FEBS letters, 1998
In the mouse fibrosarcoma cell line L929sA, tumor necrosis factor (TNF) stimulates activation of the stressresponsive p38 mitogen-activated protein kinase (MAPK), as well as the classical p42 and p44 MAPK. TNF signaling can be mediated by p55 or p75 TNF receptors. Here, we demonstrate that TNF-R55 is sufficient to activate p42/p44 MAPK and p38 MAPK. Moreover, by expressing different membrane-bound or purely cytoplasmic truncations of TNF-R55, we show that the intracellular death domain of TNF-R55 is the crucial domain involved. The cytoplasmic membrane-proximal region of TNF-R55, known to induce neutral sphingomyelinase activation, is not required for activation of p38 MAPK or p42/p44 MAPK.
Molecular and Cellular Biology, 2002
The proinflammatory cytokine tumor necrosis factor alpha (TNF-␣) regulates immune responses, inflammation, and programmed cell death (apoptosis). TNF-␣ exerts its biological activities by activating multiple signaling pathways, including IB kinase (IKK), c-Jun N-terminal protein kinase (JNK), and caspases. IKK activation inhibits apoptosis through the transcription factor NF-B, whose target genes include those that encode inhibitors of both caspases and JNK. Despite activation of the antiapoptotic IKK/NF-B pathway,