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Ribosomal protein S6 is a selective mediator of TRAIL-apoptotic signaling

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

References

  • Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA et al. (1999). Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 104: 155–162.

    Article  CAS  Google Scholar 

  • Beuvink I, Boulay A, Fumagalli S, Zilbermann F, Ruetz S, O’Reilly T et al. (2005). The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 120: 747–759.

    Article  CAS  Google Scholar 

  • Fesik SW . (2005). Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 5: 876–885.

    Article  CAS  Google Scholar 

  • Franco R, Rosenfeld MG . (1990). Hormonally inducible phosphorylation of a nuclear pool of ribosomal protein S6. J Biol Chem 265: 4321–4325.

    CAS  PubMed  Google Scholar 

  • Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ . (2001). p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci USA 98: 9666–9670.

    Article  CAS  Google Scholar 

  • Inoki K, Corradetti MN, Guan KL . (2005). Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 37: 19–24.

    Article  CAS  Google Scholar 

  • Jefferies HB, Fumagalli S, Dennis PB, Reinhard C, Pearson RB, Thomas G . (1997). Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k. EMBO J 16: 3693–3704.

    Article  CAS  Google Scholar 

  • Kim IK, Chung CW, Woo HN, Hong GS, Nagata S, Jung YK . (2000). Reconstitution of caspase-8 sensitizes JB6 cells to TRAIL. Biochem Biophy Res Commun 277: 311–316.

    Article  CAS  Google Scholar 

  • Kim IK, Jung YK, Noh DY, Song YS, Choi CH, Oh BH et al. (2003). Functional screening of genes suppressing TRAIL-induced apoptosis: distinct inhibitory activities of Bcl-XL and Bcl-2. Br J Cancer 88: 910–917.

    Article  CAS  Google Scholar 

  • Krieg J, Hofsteenge J, Thomas G . (1988). Identification of the 40S ribosomal protein S6 phosphorylation sites induced by cycloheximide. J Biol Chem 263: 11473–11477.

    CAS  PubMed  Google Scholar 

  • Nebbioso A, Clarke N, Voltz E, Germain E, Ambrosino C, Bontempo P et al. (2005). Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nat Med 1: 77–84.

    Article  Google Scholar 

  • Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM . (1997a). An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 277: 815–818.

    Article  CAS  Google Scholar 

  • Pan G, O’Rouke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J et al. (1997b). The receptor for the cytotoxic ligand TRAIL. Science 276: 111–113.

    Article  CAS  Google Scholar 

  • Panner A, James CD, Berger MS, Pieper RO . (2005). mTOR controls FLIPS translation and TRAIL sensitivity in glioblastoma multiforme cells. Mol Cell Biol 25: 8809–8823.

    Article  CAS  Google Scholar 

  • Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J et al. (2004). S6K1(−/−)/S6K2(−/−) mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol 24: 3112–3124.

    Article  CAS  Google Scholar 

  • Pitti RM, Marsters SA, Ruppert A, Donahue CJ, Moore A, Ashkenazi A . (1996). Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 271: 12687–12690.

    Article  CAS  Google Scholar 

  • Raymond AD, Helen T, Fiona CK, Xue SL, Juthathip M, Paul CE et al. (2005). Expression of TRAIL and TRAIL receptors in normal and malignant tissues. Cell Res 15: 430–438.

    Article  Google Scholar 

  • Ren YG, Klaus WW, Deborah AK, Pedro AB, Marc N, Quinn LD . (2004). Differential regulation of the TRAIL death receptors DR4 and DR5 by the signal recognition particle. Mol Cell Biol 15: 5064–5074.

    Article  CAS  Google Scholar 

  • Ruvinsky I, Sharon N, Lerer T, Cohen H, Stolovich-Rain M, Nir T et al. (2005). Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. Genes Dev 19: 2199–2211.

    Article  CAS  Google Scholar 

  • Shashirekha S, Bonnie AG, Jennifer GB, Xiaojie H, Nicolette VY, Gary H et al. (2005). Transcription factor NF-κB differentially regulates death receptor 5 expression involving histone deacetylase 1. Mol Cell Biol 25: 5404–5416.

    Article  Google Scholar 

  • Sheridan JP, Marsters SE, Pitti RM, Gurney A, Skubatch M, Baldwin D et al. (1997). Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277: 818–821.

    Article  CAS  Google Scholar 

  • Stromberg T, Dimberg A, Hammarberg A, Carlson K, Osterborg A, Nilsson K et al. (2004). Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone. Blood 103: 3138–3147.

    Article  Google Scholar 

  • Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK . (1995). Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3: 673–682.

    Article  CAS  Google Scholar 

  • Wu GS, Burns TF, McDonald III ER, Jiang W, Meng R, Krantz ID et al. (1997). KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet 17: 141–143.

    Article  CAS  Google Scholar 

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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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Correspondence to Y-K Jung.

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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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