Negative feedback regulation by HuR controls TRIM21 expression and function in response to UV radiation.
3' Untranslated Regions
Base Sequence
Binding Sites
Breast Neoplasms
Cell Line, Tumor
Cell Proliferation
ELAV-Like Protein 1
/ metabolism
Female
Gene Expression Regulation
/ radiation effects
Humans
Models, Biological
Nucleic Acid Conformation
Protein Binding
Protein Biosynthesis
Ribonucleoproteins
/ genetics
Ultraviolet Rays
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
16 07 2020
16 07 2020
Historique:
received:
11
10
2019
accepted:
22
05
2020
entrez:
18
7
2020
pubmed:
18
7
2020
medline:
18
12
2020
Statut:
epublish
Résumé
The E3 ubiquitin ligase TRIM21 plays a crucial role as a negative regulator of innate immune responses. Recent evidence has also indicated the involvement of TRIM21 in the genotoxic stress response and suppressing tumorigenesis. Our previous work has demonstrated a new function of TRIM21 in inhibiting p53 protein synthesis by degrading the RNA-binding protein HuR in response to UV radiation. This suggested a pro-oncogenic role of TRIM21. In this study, we have shown that TRIM21 enhances the proliferation of MCF7 breast carcinoma cells and counteracts the decrease in cell proliferation and colony formation caused by UV-induced DNA damage. Further, this pro-oncogenic role of TRIM21 in response to DNA damage is mediated by its degradation of HuR. Conversely, we found that HuR binds to a U-rich element in the 3'UTR of TRIM21 mRNA and activates its translation, thereby constituting a negative feedback loop. We found that dihydrotanshinone-I (DHTS-I), a plant-derived product which prevents HuR binding to specific RNAs, prevented HuR-mediated upregulation of TRIM21, while increasing the HuR-mediated upregulation of p53. Together, these findings demonstrate a negative feedback regulation between TRIM21 and HuR, which may play an important role in regulating the level of p53 in the genotoxic stress response.
Identifiants
pubmed: 32678213
doi: 10.1038/s41598-020-68646-3
pii: 10.1038/s41598-020-68646-3
pmc: PMC7367240
doi:
Substances chimiques
3' Untranslated Regions
0
ELAV-Like Protein 1
0
ELAVL1 protein, human
0
Ribonucleoproteins
0
SS-A antigen
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
11753Références
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