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Ubiquitylation of p53 by the APC/C inhibitor Trim39
- Source :
- Proceedings of the National Academy of Sciences. 109:20931-20936
- Publication Year :
- 2012
- Publisher :
- Proceedings of the National Academy of Sciences, 2012.
-
Abstract
- Tripartite motif 39 (Trim39) is a RING domain-containing E3 ubiquitin ligase able to inhibit the anaphase-promoting complex (APC/C) directly. Through analysis of Trim39 function in p53-positive and p53-negative cells, we have found, surprisingly, that p53-positive cells lacking Trim39 could not traverse the G1/S transition. This effect did not result from disinhibition of the APC/C. Moreover, although Trim39 loss inhibited etoposide-induced apoptosis in p53-negative cells, apoptosis was enhanced by Trim39 knockdown in p53-positive cells. Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation. Depletion of Trim39 significantly increased p53 protein levels and cell growth retardation in multiple cell lines. We found that the relative importance of Trim39 and the well-characterized p53-directed E3 ligase, murine double minute 2 (MDM2), varied between cell types. In cells that were relatively insensitive to the MDM2 inhibitor, nutlin-3a, apoptosis could be markedly enhanced by siRNA directed against Trim39. As such, Trim39 may serve as a potential therapeutic target in tumors with WT p53 when MDM2 inhibition is insufficient to elevate p53 levels and apoptosis.
- Subjects :
- Cyclin-Dependent Kinase Inhibitor p21
DNA Replication
Cell type
Ubiquitin-Protein Ligases
Amino Acid Motifs
Apoptosis
Anaphase-Promoting Complex-Cyclosome
Ubiquitin
Humans
RNA, Small Interfering
Cell Proliferation
Multidisciplinary
biology
Cell growth
Cell Cycle
G1 Phase
Ubiquitination
Ubiquitin-Protein Ligase Complexes
Biological Sciences
Cell cycle
Flow Cytometry
Molecular biology
Ubiquitin ligase
Cell biology
Cell culture
biology.protein
Mdm2
Tumor Suppressor Protein p53
Carrier Proteins
Protein Binding
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 109
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....04f50840ab06ba27d15cae8de541c51e