Mitogen-activated Protein Kinase Kinase Antagonized Fas-associated Death Domain Protein–mediated Apoptosis by Induced FLICE-inhibitory Protein Expression

Abstract

Fas and Fas-associated death domain (FADD) play a critical role in the homeostasis of different cell types. The regulation of Fas and FADD-mediated cell death is pivotal to many physiological functions. The activation of T lymphocytes by concanavalin A (Con A) inhibited Fas-mediated cell death. We identified that among the several activation signals downstream of Con A stimulation, mitogen-activated protein (MAP) kinase kinase (MKK) was the major kinase pathway that antagonized Fas-triggered cell death. MKK1 suppressed FADD- but not caspase-3– induced apoptosis, indicating that antagonism occurred early along the Fas-initiated apoptotic cascade. We further demonstrated that activation of MKK1 led to expression of FLIP, a specific inhibitor of FADD. MKK1 inhibition of FADD-induced cell death was abrogated if induction of FLIP was prevented, indicating that FLIP mediates MKK1 suppression of FADD-mediated apoptosis. Our results illustrate a general mechanism by which activation of MAP kinase attenuates apoptotic signals initiated by death receptors in normal and transformed cells.

Activation of protein kinase C inhibits TRAIL-induced caspases activation, mitochondrial events and apoptosis in a human leukemic T cell line

“…30 However, more recent results show no correlation between FLIP expression and resistance to TRAIL in these tumor cells. 78 Although MAPK stimulation in Jurkat T cells with concanavalin A has recently been reported to induce FLIP, 54 we however have found no changes in FLIP (L/S) or IAPs mRNA expression when Jurkat cells are treated with PDBu. These results support our data with CHX in which we show that the PDBu-mediated inhibitory action is protein synthesisindependent.…”

The mitogen-activated protein kinase pathway can inhibit TRAIL-induced apoptosis by prohibiting association of truncated Bid with mitochondria

“…30 Furthermore, it has been reported that Bcl-2 expression is upregulated by Erk 31 and that the MAPK pathway could antagonize death receptor-mediated apoptosis by inducing FLICE-inhibitory protein (cFLIP) expression. 32 However, our results indicate that the apoptosis antagonizing effect of a PKC/MAPK activator does not require de novo protein synthesis. Several authors have shown that MAPK pathway protects from apoptosis triggered by different stimuli at the level of mitochondria.…”

Activation of extracellular signal-regulated protein kinase 5 downregulates FasL upon osmotic stress

“…32 Its ability to increase the expression of the FLICElike inhibitory protein FLIP suppresses sensitivity towards FasL-mediated apoptosis by preventing caspase 8 activation independently of PKB signaling. 33 The relative importance of ERK1/2 and ERK5 in mediating cell survival is likely to be stimulus-and cell type-specific. For example, whereas ERK1/ 2 and ERK5 are both required for mediating neuronal survival in response to NGF, 34 ERK5 is critical for the survival of endothelial cells during development.…”