Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2.
Acetylation
Antibiotics, Antineoplastic
/ pharmacology
Antineoplastic Agents
/ pharmacology
Bleomycin
/ toxicity
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cisplatin
/ pharmacology
DNA Damage
/ drug effects
Gene Expression Regulation, Neoplastic
/ drug effects
Gene Knockdown Techniques
Humans
Phosphorylation
Promoter Regions, Genetic
Protein Binding
Protein Stability
Proto-Oncogene Proteins c-mdm2
/ genetics
RNA, Small Interfering
Signal Transduction
/ genetics
Tumor Suppressor Protein p53
/ genetics
Ubiquitin-Protein Ligases
/ genetics
DNA damage
HERC2
MDM2
NEURL4
p53
tumor suppressor
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
22
05
2019
revised:
30
09
2019
accepted:
28
10
2019
pubmed:
31
10
2019
medline:
4
2
2021
entrez:
31
10
2019
Statut:
ppublish
Résumé
The p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally regulated by p53 in a negative feedback loop. The p53 protein is transcriptionally active as a tetramer, and this oligomerization state is modulated by a complex formed by NEURL4 and the ubiquitin E3 ligase HERC2. Here, we report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its protein stability, as it reduces its mRNA expression by inhibition of its promoter activation. DNA damage induced by bleomycin dissociates MDM2 from the p53/HERC2/NEURL4 complex and increases the phosphorylation and acetylation of oligomeric p53 bound to HERC2 and NEURL4. Moreover, the MDM2 promoter, which contains p53-response elements, competes with HERC2 for binding of oligomeric, phosphorylated and acetylated p53. We integrate these findings in a model showing the pivotal role of HERC2 in p53-MDM2 loop regulation. Altogether, these new insights in p53 pathway regulation are of great interest in cancer and may provide new therapeutic targets.
Identifiants
pubmed: 31665549
doi: 10.1002/1878-0261.12592
pmc: PMC6944118
doi:
Substances chimiques
Antibiotics, Antineoplastic
0
Antineoplastic Agents
0
RNA, Small Interfering
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Bleomycin
11056-06-7
HERC2 protein, human
EC 2.3.2.27
MDM2 protein, human
EC 2.3.2.27
Neurl4 protein, human
EC 2.3.2.27
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
69-86Informations de copyright
© 2019 The Authors. Molecular Oncology published by John Wiley & Sons Ltd.
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