MAPK/ERK Overrides the Apoptotic Signaling from Fas, TNF, and TRAIL Receptors

Abstract

The tumor necrosis factor (TNF), Fas, and TNF-related apoptosis-inducing ligand (TRAIL) receptors (R) are highly specific physiological mediators of apoptotic signaling. We observed earlier that a number of FasR-insensitive cell lines could redirect the proapoptotic signal to an anti-apoptotic ERK1/2 signal resulting in inhibition of caspase activation. Here we determine that similar mechanisms are operational in regulating the apoptotic signaling of other death receptors. Activation of the FasR, TNF-R1, and TRAIL-R, respectively, rapidly induced subsequent ERK1/2 activation, an event independent from caspase activity. Whereas inhibition of the death receptor-mediated ERK1/2 activation was sufficient to sensitize the cells to apoptotic signaling from FasR and TRAIL-R, cells were still protected from apoptotic TNF-R1 signaling. The latter seemed to be due to the strong activation of the anti-apoptotic factor NF-B, which remained inactive in FasR or TRAIL-R signaling. However, when the cells were sensitized with cycloheximide, which is sufficient to sensitize the cells also to apoptosis by TNF-R1 stimulation, we noticed that adenovirus-mediated expression of constitutively active MKK1 could rescue the cells from apoptosis induced by the respective receptors by preventing caspase-8 activation. Taken together, our results show that ERK1/2 has a dominant protecting effect over apoptotic signaling from the death receptors. This protection, which is independent of newly synthesized proteins, acts in all cases by suppressing activation of the caspase effector machinery.

Identification of Siah-interacting protein as a potential regulator of apoptosis and curcumin resistance

“…Besides, SIP has been found to interact with ERK1/2 and downregulate ERK activity (Kilanczyk et al, 2009). Furthermore, suppression of the ERK-involved pathway sensitizes cancer cells to apoptosis (Tran et al, 2001;Wu et al, 2004) and a series of inhibitors targeting ERK pathway have been identified as potential anti-cancer drugs (Daouti et al, 2009). It has also been shown that SIP serves as a molecular bridge between Siah-1 and Skp1 proteins, and forms a ubiquitin ligase complex together with Ebi and in turn promotes b-catenin degradation.…”

Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Signaling in Activated T Cells Abrogates TRAIL-Induced Apoptosis Upstream of the Mitochondrial Amplification Loop and Caspase-8

“…In this respect, especially the classical mitogen-activated protein kinase (MAPK) signaling pathway has been implicated as a dominant negative regulator of DR-mediated apoptosis. We have observed that MAPK/extracellular signal-regulated kinase (ERK) signaling potently modifies FasR responses (34,35) and found indications that it is involved in regulating also TRAIL-R responses (36). We have also shown that MAPK/ERK signaling from the TCR is able to protect T cells from FasR-mediated apoptosis (37) before they commit activation-induced cell death (AICD).…”

“…It is well known that several cell lines can be sensitized to DRmediated apoptosis by pretreatment with protein synthesis inhibitors (36). This raises the possibility that the MAPK/ERK-mediated effect could be protein synthesis dependent.…”

Hexamethylene Bisacetamide (HMBA) simultaneously targets AKT and MAPK pathway and represses NF-κB activity: Implications for cancer therapy

“…HMBA downregulates NFκB pathway is another important pathway involved in cell survival [21][22][23] and has been shown to activate NFκB responses by activation of p90 Rsk. [24][25][26][27] In an effort to understand the mechanism of action of HMBA, we investigated its effect on the NFκB pathway.…”