The Csdependent Apoptotic Signal Is Transduced By Jnk And p38 Mapk Pathways

Data from the literature describing stress-induced apoptosis by an autocrine mechanism in T-cells link stress-mediated fasL expression, with the prior activation of the Jun-N-term-inal kinase (JNK) signaling pathway when cells were exposed to genotoxic physical stresses (34) and with the activation of the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway when the cells were challenged with inhibitors of protein synthesis (35). In turn, both pathways are supposed to convey their signal to the transcription factor AP-1, specifically composed of ATF-2 and c-Jun proteins, eventually leading to the transcriptional activation of fasL (36).

Investigation of CS-exposed Swiss 3T3 cells for activated JNK and p38 MAPK signal transduction pathways by screening the cells for phosphorylated JNK and p38 MAPK proteins revealed a strong activation of both pathways. Activated JNK and p38 MAPK proteins were first seen after 30-60 min, but were still clearly detectable after 8 hr of exposure. Considering that CS has been shown to exert both genotoxic effects (6) and protein synthesis inhibitory effects (2), the activation of both pathways by CS is conceivable. In addition to activated JNK and p38 MAPK signaling, increased protein binding to model nucleotides containing an AP-1/TPA-responsive element (TRE) consensus binding site was observed in protein extracts from CS-exposed cells, while virtually no increase was observed in the amount of pre-existing DNA protein complexes when an AP-1/cAMP response element (CRE)-specific oligonucleotide, which is more efficiently recognized by c-Jun/ATF-2 heterodimers (37), was used for analysis. However, the trans-activation activity of AP-1, composed of c-Jun/ATF-2, is mainly determined by phosphorylation rather than by a considerable effect on the DNA-binding activity (37). In fact, the specific activation of c-Jun/ATF-2 as a potential trans-activator of fasL expression in CS-exposed cells was readily observed when the cells were monitored for phosphorylated c-Jun and ATF-2. As revealed by Western blotting, both activated proteins produced strong signals, which were first detectable approximately 30min after the start of exposure.

Finally, the crucial involvement of the JNK as well as the p38 MAPK signaling pathways in CS-induced apoptosis were demonstrated when SV-pretreated Swiss 3T3 cells were quantified for apoptosis formation in the presence of specific inhibitors of either JNK (SP600125) or p38 MAPK (SB 203580): a significant (~60%) reduction in the amount of apoptotic cells was discernable for either inhibitor, clearly indicating that apoptosis of CS-exposed Swiss 3T3 cells with impaired HO-1 expression is dependent on activation of JNK and p38 MAPK stress signal transduction (32).

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Detox Diet Basics

Detox Diet Basics

Our internal organs, the colon, liver and intestines, help our bodies eliminate toxic and harmful  matter from our bloodstreams and tissues. Often, our systems become overloaded with waste. The very air we breathe, and all of its pollutants, build up in our bodies. Today’s over processed foods and environmental pollutants can easily overwhelm our delicate systems and cause toxic matter to build up in our bodies.

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