Abstract
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a potent inducer of apoptosis in tumor cells and holds a promise as a therapeutic agent against cancer. To elucidate the death signaling evoked by TRAIL, we performed a functional genetic screening and rescued TRAIL-resistant Jurkat clones harboring ribosomal protein S6 (rpS6) cDNA in anti-sense frame. Reduction of rpS6 expression in Jurkat and HeLa cells attenuated apoptosis induced by TRAIL, but not those by other cell death signals, including tumor necrosis factor-α and cycloheximide, etoposide, doxorubicin, tunicamycin and staurosporine. Death receptor (DR) 4, but not DR5, was downregulated in rpS6 knockdown cells. Conversely, the sensitivity to TRAIL was increased by the ectopic expression of wild-type rpS6 and further by phospho-defective rpS6 mutant (S6-SS235,6AA), but not by phospho-mimic rpS6 mutant (S6-SS235,6DD). Also, unphosphorylatable rpS6 knock-in mouse embryo fibroblasts (rpS6P−/− MEFs) were more sensitive to TRAIL than control MEFs. In addition, SKHep-1 tumor cells, which express less phospho-rpS6 and are more sensitive to TRAIL than other tumor cells, became effectively desensitized to TRAIL after rpS6 knockdown. These results suggest that rpS6, especially in its unphosphorylated form, is a selective mediator of TRAIL-induced apoptosis.
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Abbreviations
- CHX:
-
cycloheximide
- DR4/DR5:
-
death receptor 4/5
- mTOR:
-
mammalian target of rapamycin
- rpS6:
-
ribosomal protein S6
- rpS6P−/− MEFs:
-
unphosphorylatable rpS6 knock-in mouse embryonic fibroblast
- shRNA:
-
short hairpin RNA
- TRAIL:
-
tumor necrosis factor-related apoptosis-inducing ligand
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Acknowledgements
We thank Dr JO Pyo for technical assistance. SH Hong and HJ Kim were supported by BK21 program. This work was supported by the grant from Korean Research Foundation (KRF-2005-201-C00039), Human Genomics of 21C Frontier Research Program Nuclear Research Grant (M2070800000-07130800-0010) and Functional Cellulomics funded by the Korea Science and Engineering Foundation (KOSEF).
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
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Jeon, YJ., Kim, I., Hong, SH. et al. Ribosomal protein S6 is a selective mediator of TRAIL-apoptotic signaling. Oncogene 27, 4344–4352 (2008). https://doi.org/10.1038/onc.2008.73
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DOI: https://doi.org/10.1038/onc.2008.73
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