Abstract
TNF-related apoptosis-inducing ligand (TRAIL) receptor 2 (TRAIL-R2) can induce apoptosis in cancer cells upon crosslinking by TRAIL. However, TRAIL-R2 is highly expressed by many cancers suggesting pro-tumor functions. Indeed, TRAIL/TRAIL-R2 also activate pro-inflammatory pathways enhancing tumor cell invasion, migration, and proliferation. In addition, nuclear TRAIL-R2 (nTRAIL-R2) promotes malignancy by inhibiting miRNA let-7-maturation. Here, we show that TRAIL-R2 interacts with the tumor suppressor protein p53 in the nucleus, assigning a novel pro-tumor function to TRAIL-R2. Knockdown of TRAIL-R2 in p53 wild-type cells increases the half-life of p53 and the expression of its target genes, whereas its re-expression decreases p53 protein levels. Interestingly, TRAIL-R2 also interacts with promyelocytic leukemia protein (PML), a major regulator of p53 stability. PML-nuclear bodies are also the main sites of TRAIL-R2/p53 co-localization. Notably, knockdown or destruction of PML abolishes the TRAIL-R2-mediated regulation of p53 levels. In summary, our finding that nTRAIL-R2 facilitates p53 degradation and thereby negatively regulates p53 target gene expression provides insight into an oncogenic role of TRAIL-R2 in tumorigenesis that particularly manifests in p53 wild-type tumors.
Highlights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in neoplastic cells upon binding to its receptors TRAIL-R1 and TRAIL-R2 [1, 2]
Nuclear TRAIL-R2 co-localizes with p53 Since both, TRAIL-R2 and p53 are present in the nucleus and each of them can interact with the chromatin and with the microprocessor complex, we asked whether both proteins may interact with each other within the nuclear compartment
We studied the intracellular distribution of TRAIL-R2 and p53 in wildtype p53-expressing HCT116 colon carcinoma cells by indirect immunofluorescence staining followed by confocal laser scanning microscopy (LSM)
Summary
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in neoplastic cells upon binding to its receptors TRAIL-R1 and TRAIL-R2 [1, 2]. Many tumor cells are resistant to TRAIL and TRAIL-R1/R2 can activate pro-inflammatory pathways thereby promoting invasion, migration, and metastasis [3,4,5,6,7,8,9,10,11] All these TRAIL-R-functions are linked to their presence at the plasma membrane. It was described that nuclear TRAIL-R2 negatively regulates the maturation of miRNA let-7 via interaction with the microprocessor complex and enhances tumor cell malignancy [18]. Both nuclear TRAIL-R1 (nTRAILR1) and nTRAIL-R2 are associated with chromatin suggesting their role in regulating gene expression [12]
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