Ubiquitylation of p53 by the APC/C inhibitor Trim39.

dc.contributor.author

Zhang, Liguo

dc.contributor.author

Huang, Nai-Jia

dc.contributor.author

Chen, Chen

dc.contributor.author

Tang, Wanli

dc.contributor.author

Kornbluth, Sally

dc.coverage.spatial

United States

dc.date.accessioned

2014-03-06T17:50:58Z

dc.date.issued

2012-12-18

dc.description.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.

dc.identifier

http://www.ncbi.nlm.nih.gov/pubmed/23213260

dc.identifier

1212047110

dc.identifier.eissn

1091-6490

dc.identifier.uri

https://hdl.handle.net/10161/8389

dc.language

eng

dc.publisher

Proceedings of the National Academy of Sciences

dc.relation.ispartof

Proc Natl Acad Sci U S A

dc.relation.isversionof

10.1073/pnas.1212047110

dc.subject

Amino Acid Motifs

dc.subject

Anaphase-Promoting Complex-Cyclosome

dc.subject

Apoptosis

dc.subject

Carrier Proteins

dc.subject

Cell Cycle

dc.subject

Cell Proliferation

dc.subject

Cyclin-Dependent Kinase Inhibitor p21

dc.subject

DNA Replication

dc.subject

Flow Cytometry

dc.subject

G1 Phase

dc.subject

Humans

dc.subject

Protein Binding

dc.subject

RNA, Small Interfering

dc.subject

Tumor Suppressor Protein p53

dc.subject

Ubiquitin

dc.subject

Ubiquitin-Protein Ligase Complexes

dc.subject

Ubiquitination

dc.title

Ubiquitylation of p53 by the APC/C inhibitor Trim39.

dc.type

Journal article

pubs.author-url

http://www.ncbi.nlm.nih.gov/pubmed/23213260

pubs.begin-page

20931

pubs.end-page

20936

pubs.issue

51

pubs.organisational-group

Basic Science Departments

pubs.organisational-group

Duke

pubs.organisational-group

Duke Cancer Institute

pubs.organisational-group

Institutes and Centers

pubs.organisational-group

Pharmacology & Cancer Biology

pubs.organisational-group

School of Medicine

pubs.publication-status

Published

pubs.volume

109

Files

Original bundle

Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
Zhang_Ubiquitylation of p53 by the APC-C inhibitor Trim39.pdf
Size:
702.92 KB
Format:
Adobe Portable Document Format
Description:
Published version