Trim24 targets endogenous p53 for degradation

Allton, Kendra L.; Jain, Abhinav K.; Herz, Hans-Martin; Tsai, Wen-Wei; Jung, Sung Yun; Qin, Jun; Bergmann, Andreas; Johnson, Randy L.; Barton, Michelle C.

doi:10.1073/pnas.0813177106

Cited by 245 publications

(228 citation statements)

References 42 publications

Supporting

Mentioning

220

Contrasting

Order By: Relevance

“…Aside from the observation that p53 can be degraded in MDM2-deficient mice, mutation of the known MDM2-targeted lysines on p53 does not prevent p53 ubiquitylation and degradation in cells (22). Moreover, several other E3 ligases, including another Trim family member, Trim24, are capable of promoting p53 degradation (23). An additional level of complexity stems from the ability of several of the p53-directed ligases to control each other's stability, potentially through direct interaction (24).…”

Section: Resultsmentioning

confidence: 99%

Ubiquitylation of p53 by the APC/C inhibitor Trim39

Zhang

Huang

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Ubiquitylation of p53 by the APC/C inhibitor Trim39

Zhang

Huang

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Several new E3 ubiquitin ligases that promote degradation of p53 have been discovered, including Pirh2 (Leng et al 2003;Sheng et al 2008), Cop1 (Dornan et al 2004), TOPORS (Rajendra et al 2004), ARF-BP1 (Chen et al 2005), CARPs (Yang and El-Deiry 2007), and TRIM24 (Allton et al 2009;Tai and Benchimol 2009). The interaction pattern of Pirh2 with p53 is fundamentally different from that of MDM2 and MDMX.…”

Section: Targeting the P53 Pathway: Mdm2 Mdmx Sirtuins And Beyondmentioning

confidence: 99%

The Tumor Suppressor p53: From Structures to Drug Discovery

Joerger

Fersht²

2010

Cold Spring Harbor Perspectives in Biology

299

280

View full text Add to dashboard Cite

Even 30 years after its discovery, the tumor suppressor protein p53 is still somewhat of an enigma. p53's intimate and multifaceted role in the cell cycle is mirrored in its equally complex structural biology that is being unraveled only slowly. Here, we discuss key structural aspects of p53 function and its inactivation by oncogenic mutations. Concerted action of folded and intrinsically disordered domains of the highly dynamic p53 protein provides binding promiscuity and specificity, allowing p53 to process a myriad of cellular signals to maintain the integrity of the human genome. Importantly, progress in elucidating the structural biology of p53 and its partner proteins has opened various avenues for structure-guided rescue of p53 function in tumors. These emerging anticancer strategies include targeting mutant-specific lesions on the surface of destabilized cancer mutants with small molecules and selective inhibition of p53's degradative pathways.

show abstract

“…For example, Bonus is a homolog of TRIM 24, a p53 ligase in vertebrates. The results from loss-offunction studies indicated that Bonus is critical for maintaining p53 activity in Drosophila, suggesting that Bonus might be an evolutionarily conserved E3 ligase for p53 (14). The existence of multiple E3 ligases for p53 strongly suggests that specialization among them must be required for controlling p53 at multiple levels in different regulatory programs.…”

mentioning

confidence: 97%

RNF2/Ring1b negatively regulates p53 expression in selective cancer cell types to promote tumor development

Fang

Cheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Large numbers of studies have focused on the posttranslational regulation of p53 activity. One of the best-known negative regulators for p53 is MDM2, an E3 ubiquitin ligase that promotes p53 degradation through proteasome degradation pathways. Additional E3 ligases have also been reported to negatively regulate p53. However, whether these E3 ligases have distinct/overlapping roles in the regulation of p53 is largely unknown. In this study, we identify RNF2 (ring finger protein 2) as an E3 ligase that targets p53 for degradation. The E3 ligase activity of RNF2 requires Bmi1 protein, a component of the polycomb group (PcG) complex. The up-regulation of p53 does not affect RNF2 expression. Unlike Mdm2, RNF2 only degrades p53 in selective cell lines, such as those from germ-cell tumors. The knockdown of RNF2 induces apoptosis, which can be rescued through the reduction of p53 expression. Moreover, the down-regulation of RNF2 expression in germ-cell tumors significantly reduces tumor cell growth, while the simultaneous down-regulation of both genes restores tumor cell growth in vitro and in tumor xenograft models. Furthermore, a reverse correlation between RNF2 and p53 expression was detected in human ovarian cancer tissues. Together, these results indicate that RNF2 is an E3 ligase for p53 degradation in selective cells, implicating RNF2 as a therapeutic target to restore tumor suppression through p53 in certain tumor cells.

show abstract

Trim24 targets endogenous p53 for degradation

Cited by 245 publications

References 42 publications

Ubiquitylation of p53 by the APC/C inhibitor Trim39

Ubiquitylation of p53 by the APC/C inhibitor Trim39

The Tumor Suppressor p53: From Structures to Drug Discovery

RNF2/Ring1b negatively regulates p53 expression in selective cancer cell types to promote tumor development

Contact Info

Product

Resources

About