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Tristetraprolin Posttranscriptionally Downregulates TRAIL Death Receptors

1
Department of Otorhinolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea
2
Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Korea
3
Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
4
Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
5
Department of Otorhinolaryngology, GangNeung Asan Hospital, University of Ulsan College of Medicine, Gangneung 25440, Korea
*
Authors to whom correspondence should be addressed.
Cells 2020, 9(8), 1851; https://doi.org/10.3390/cells9081851
Received: 24 June 2020 / Revised: 31 July 2020 / Accepted: 4 August 2020 / Published: 7 August 2020
(This article belongs to the Section Cell Signaling)
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has attracted attention as a potential candidate for cancer therapy. However, many primary cancers are resistant to TRAIL, even when combined with standard chemotherapy. The mechanism of TRAIL resistance in cancer cells has not been fully elucidated. The TRAIL death receptor (DR) 3′-untranslated region (3′-UTR) is reported to contain AU-rich elements (AREs) that are important for regulating DR mRNA stability. However, the mechanisms by which DR mRNA stability is determined by its 3′-UTR are unknown. We demonstrate that tristetraprolin (TTP), an ARE-binding protein, has a critical function of regulating DR mRNA stability. DR4 mRNA contains three AREs and DR5 mRNA contains four AREs in 3′-UTR. TTP bound to all three AREs in DR4 and ARE3 in DR5 and enhanced decay of DR4/5 mRNA. TTP overexpression in colon cancer cells changed the TRAIL-sensitive cancer cells to TRAIL-resistant cells, and down-regulation of TTP increased TRAIL sensitivity via DR4/5 expression. Therefore, this study provides a molecular mechanism for enhanced levels of TRAIL DRs in cancer cells and a biological basis for posttranscriptional modification of TRAIL DRs. In addition, TTP status might be a biomarker for predicting TRAIL response when a TRAIL-based treatment is used for cancer. View Full-Text
Keywords: tumor necrosis factor-related apoptosis-inducing ligand; death receptor; tristetraprolin; posttranscriptional modification; AU-rich elements; cancer treatment tumor necrosis factor-related apoptosis-inducing ligand; death receptor; tristetraprolin; posttranscriptional modification; AU-rich elements; cancer treatment
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MDPI and ACS Style

Lee, W.H.; Han, M.W.; Kim, S.H.; Seong, D.; An, J.H.; Chang, H.W.; Kim, S.Y.; Kim, S.W.; Lee, J.C. Tristetraprolin Posttranscriptionally Downregulates TRAIL Death Receptors. Cells 2020, 9, 1851. https://doi.org/10.3390/cells9081851

AMA Style

Lee WH, Han MW, Kim SH, Seong D, An JH, Chang HW, Kim SY, Kim SW, Lee JC. Tristetraprolin Posttranscriptionally Downregulates TRAIL Death Receptors. Cells. 2020; 9(8):1851. https://doi.org/10.3390/cells9081851

Chicago/Turabian Style

Lee, Won H., Myung W. Han, Song H. Kim, Daseul Seong, Jae H. An, Hyo W. Chang, Sang Y. Kim, Seong W. Kim, and Jong C. Lee 2020. "Tristetraprolin Posttranscriptionally Downregulates TRAIL Death Receptors" Cells 9, no. 8: 1851. https://doi.org/10.3390/cells9081851

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