TRAIL-receptor 2-a novel negative regulator of p53

Cell Death Dis. 2021 Jul 31;12(8):757. doi: 10.1038/s41419-021-04048-1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Humans
  • Promyelocytic Leukemia Protein / metabolism
  • Protein Binding
  • Protein Stability
  • Protein Transport
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • Promyelocytic Leukemia Protein
  • RNA, Messenger
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2
  • Caspases