Mert, Ufuk and Adawy, Alshaimaa and Scharff, Elisabeth and Teichmann, Pierre and Willms, Anna and Haselmann, Verena and Colmorgen, Cynthia and Lemke, Johannes and von Karstedt, Silvia and Fritsch, Juergen and Trauzold, Anna (2019) TRAIL Induces Nuclear Translocation and Chromatin Localization of TRAIL Death Receptors. CANCERS, 11 (8): 1167. ISSN , 2072-6694
Full text not available from this repository. (Request a copy)Abstract
Binding of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to the plasma membrane TRAIL-R1/-R2 selectively kills tumor cells. This discovery led to evaluation of TRAIL-R1/-R2 as targets for anti-cancer therapy, yet the corresponding clinical trials were disappointing. Meanwhile, it emerged that many cancer cells are TRAIL-resistant and that TRAIL-R1/R2-triggering may lead to tumor-promoting effects. Intriguingly, recent studies uncovered specific functions of long ignored intracellular TRAIL-R1/-R2, with tumor-promoting functions of nuclear (n)TRAIL-R2 as the regulator of let-7-maturation. As nuclear trafficking of TRAIL-Rs is not well understood, we addressed this issue in our present study. Cell surface biotinylation and tracking of biotinylated proteins in intracellular compartments revealed that nTRAIL-Rs originate from the plasma membrane. Nuclear TRAIL-Rs-trafficking is a fast process, requiring clathrin-dependent endocytosis and it is TRAIL-dependent. Immunoprecipitation and immunofluorescence approaches revealed an interaction of nTRAIL-R2 with the nucleo-cytoplasmic shuttle protein Exportin-1/CRM-1. Mutation of a putative nuclear export sequence (NES) in TRAIL-R2 or the inhibition of CRM-1 by Leptomycin-B resulted in the nuclear accumulation of TRAIL-R2. In addition, TRAIL-R1 and TRAIL-R2 constitutively localize to chromatin, which is strongly enhanced by TRAIL-treatment. Our data highlight the novel role for surface-activated TRAIL-Rs by direct trafficking and signaling into the nucleus, a previously unknown signaling principle for cell surface receptors that belong to the TNF-superfamily.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | FACTOR-BETA RECEPTOR; BREAST-CANCER CELLS; NF-KAPPA-B; LIGAND TRAIL; TUMORICIDAL ACTIVITY; EXPORT SIGNALS; APOPTOSIS; RESISTANCE; PROTEIN; ACTIVATION; TRAIL; nuclear TRAIL-R1; nuclear TRAIL-R2; trafficking; CRM-1 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 Apr 2020 11:54 |
| Last Modified: | 06 Apr 2020 11:54 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26487 |
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