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Trimming P53 for Ubiquitination COMMENTARY TRIMming p53 for ubiquitination Elizabeth Taia and Samuel Benchimolb,1 aDepartment of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5S 3L1; and bDepartment of Biology, York University, Toronto, ON, Canada M3J 1P3 he function of the p53 tumor Table 1. A comparison of the E3 ubiquitin ligases that target p53 for degradation suppressor protein is finely Degradation of p53 tuned through a myriad of in- E3 ligase Type p53-responsive after DNA damage Phosphorylation Ref. teractions with other proteins. TThese interactions can lead to posttrans- Mdm2 RING Yes No Ser-166, Ser-188, 1, 2 lational modifications that regulate p53 Ser-395; Tyr-276, stability, DNA binding, or promoter- Tyr-394* specific transcriptional activation. A Pirh2 RING Yes Thr-154; Ser-155† 10,18 number of p53 binding proteins serve as Cop1 RING Yes No Ser-387‡ 11,17 cofactors that participate in the recruit- ARF-BP1 HECT 12 ment of p53 to specific promoters and CARP1/2§ RING Yes 14 facilitate transcriptional activation by TOPORS RING 13 p53. Other p53-interacting proteins reg- Synoviolin RING 15 ulate transcription-independent activities TRIM24 RING Yes 3 of p53 and p53 subcellular localization (reviewed in refs. 1 and 2). A new p53 *ATM-mediated phosphorylation of Mdm2 on Ser-395 decreases the ability of Mdm2 to degrade p53. Wip1 phosphatase dephosphorylates Ser-395 on Mdm2 to increase the degradation of p53 by Mdm2. binding partner is identified by Allton et Akt/PKB-mediated phosphorylation of Mdm2 on Ser-166 and Ser-188 stabilizes Mdm2. These phosphor- al. (3) in this issue of PNAS, and it ylation sites also appear to be necessary for translocation of Mdm2 from the cytoplasm into the nucleus. turns out to be a member of the tripar- c-Abl-mediated phosphorylation of Mdm2 on Tyr-276 and Tyr-394 after DNA damage decreases the tite motif protein (TRIM) family, ability of Mdm2 to degrade p53. TRIM24. †Pirh2 interacts with calmodulin and is phosphorylated by calmodulin-dependent kinase II on Thr-154 and The TRIM family of proteins is de- Ser-155, resulting in a decrease in Pirh2 stability and decreased degradation of p53 (18). fined by the presence of an N-terminal ‡ATM-mediated phosphorylation of Cop1 on Ser-387 after DNA damage results in the dissociation of Cop1 from p53 (17). tripartite motif composed of a RING § domain, 1 or 2 B-box motifs, and a CARP1 and CARP2 can ubiquitinate Ser-20-phosphorylated p53 after DNA damage. coiled-coil region (4). Humans have 60 TRIM genes, and these encode proteins TRIM24 and p53 interact in various ther studies are required to determine that can be further classified on the ba- cells, shRNA-mediated repression of the physical and functional interactions sis of 1 or 2 additional C-terminal do- TRIM24 causes endogenous p53 protein between these 2 families of proteins. mains. One subgroup, consisting of levels to rise, and TRIM24 promotes Unlike Mdm2-deficient mice, Trim24- TRIM24, TRIM28, and TRIM33 [also p53 ubiquitination and degradation. deficient mice are viable and fertile (8). known as transcription intermediary fac- They conclude that TRIM24 functions Trim24-deficient mice also exhibit in- tor 1 (TIF1) ␣, TIF1␤, and TIF1␥, re- as an E3 ubiquitin ligase for p53. Sec- creased hepatocellular proliferation as a spectively], contains a PHD domain fol- ond, Allton et al. performed a genetic lowed by a BROMO domain at the C result of deregulated retinoic acid sig- mosaic analysis on Drosophila imaginal terminus. These domains are important naling mediated by retinoic acid recep- discs in which they analyzed GFP- ␣ for binding to chromatin and are in- tor . Trim24-deficient mice also exhibit bonus volved in transcriptional repression. marked homozygous mutant cells a high incidence of hepatocellular carci- in a heterozygous bonus strain. GFP- noma probably as a consequence of un- TRIM24 protein interacts with retinoic Ϫ/Ϫ acid receptors in a ligand-dependent positive bonus cells appeared small controlled and continuous hepatocyte fashion to regulate their transcriptional and highly apoptotic. Remarkably, proliferation. In a ras-induced liver car- activity. TRIM proteins are conserved RNAi-mediated depletion of Drosophila cinoma model, endogenous p53 was in vertebrates and invertebrates (5). p53 (D-p53) rescued the bonus apopto- shown to block tumor development Drosophila has 7 TRIM-related genes, tic phenotype and resulted in bonus through the induction of cellular senes- one of which, bonus, encodes a PHD clones of larger size. This result is remi- cence (9). If Trim24-deficient hepato- and a BROMO domain downstream of niscent of the rescue of embryonic le- cytes express high levels of p53, one the tripartite motif, and is considered an thality in Mdm2-null mice conferred by would not expect to see increased cell ortholog of TRIM24/28/33. loss of p53, a key finding that estab- proliferation leading to tumor develop- The article by Allton et al. (3) is no- lished the physiological importance of ment. The relationship, if any, between table for 2 reasons. First, Allton et al. Mdm2 as a negative regulator of p53 (6, Trim24 and p53 in the liver may be developed a new knockin mouse and 7). The results by Allton et al. suggest complex and only highlights the need to stem cell model based on tandem affin- that bonus is a key regulator of D-p53 examine endogenous p53 protein levels ity purification (TAP)-tag fusion with activity. One expects that D-p53 protein not only in the liver but in other tissues the ORF of the mouse p53 gene. The levels will be elevated in homozygous of Trim24-deficient mice. p53TAP fusion protein allows TAP and bonus mutant cells but that remains to analysis of p53 protein partners by mass be determined. Extending the relation- spectrometry. With extracts prepared ship between bonus and D-p53 to mam- Author contributions: E.T. and S.B. wrote the paper. from ES cells expressing the p53TAP mals is complicated by the fact that D- The authors declare no conflict of interest. knockin allele, Trim24 copurified with p53 is the sole ortholog for p53, p63, See companion paper on page 11612. p53TAP and was identified by mass and p73, and bonus is the sole ortholog 1To whom correspondence should be addressed. E-mail: spectrometry. Allton et al. showed that for TRIM24, TRIM28, and TRIM33. Fur- [email protected]. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0905997106 PNAS ͉ July 14, 2009 ͉ vol. 106 ͉ no. 28 ͉ 11431–11432 Downloaded by guest on September 24, 2021 Trim24 joins several other ubiquitin different isoforms of p53, different oli- (2). Importantly, Mdm2 binds to various ligases (Table 1) that promote ubiquitin- gomeric forms of p53, different post- cofactors that influence its ability to mediated degradation of p53 including translationally modified forms of p53, or ubiquitinate p53 (2). Both p53 and Mdm2, Pirh2, Cop1, ARF-BP1, other p53 family members. A recent Mdm2 undergo ataxia telangiectasia TOPORS, Synoviolin, CARP1, and study (16), for example, reported that mutated (ATM)-dependent phosphory- CARP2 (1, 2, 10–15). Interference with lation in response to DNA damage, and the expression of these E3 ubiquitin li- these changes result in the dissociation gases leads to an increase in p53 stabil- The results by Allton of Mdm2 from p53 resulting in p53 pro- ity and an increase in p53-dependent tein stabilization. ATM-mediated phos- apoptosis or G1 arrest. With the excep- et al. suggest that bonus phorylation of Cop1 after DNA damage tion of Mdm2, the physiological role of similarly results in its dissociation from these ubiquitin ligases in regulating p53 is a key regulator of p53 (17), and Pirh2 stability is decreased function remains unclear, and one of the upon its phosphorylation by calmodulin- great challenges is to determine why p53 D-p53 activity. dependent kinase II (18). It will be im- is targeted for degradation through so portant to determine the lysine residues many pathways. Are the E3 ligases that on p53 that are ubiquitinated by target p53 functionally redundant? It Pirh2 preferentially targets tetrameric TRIM24 and the other E3 ligases, iden- will be important to evaluate the expres- p53, and it will be important to extend tify E3 ligase regulatory cofactors, and sion patterns of these E3 ligases during this finding to the other E3 ligases. learn how p53 ubiquitination is modu- different stages of development, in dif- Mdm2 binds p53 in unstressed cells lated through stress signals. ferent tissues, and under different stress and promotes ubiquitination on con- conditions. It is also important to deter- served C-terminal lysine residues (resi- ACKNOWLEDGMENTS. This work was supported mine whether these E3 ligases target dues 370, 372, 373, 381, 382, and 386) by Canadian Cancer Society Grant 017258. 1. Vousden KH, Prives C (2009) Blinded by the light: The 7. Montes de Oca Luna R, Wagner DS, Lozano G (1995) 13. Rajendra R, et al. (2004) Topors functions as an E3 growing complexity of p53. Cell 137:413–431. Rescue of early embryonic lethality in mdm2-deficient ubiquitin ligase with specific E2 enzymes and ubiquiti- 2. Kruse JP, Gu W (2009) Modes of p53 regulation. Cell mice by deletion of p53. Nature 378:203–206. nates p53. J Biol Chem 279:36440–36444. 137:609–622. 8. Khetchoumian K, et al. (2007) Loss of Trim24 (Tif1␣) 14. Yang W, et al. (2007) CARPs are ubiquitin ligases that 3. Allton K, et al. (2009) Trim24 targets endogenous p53 gene function confers oncogenic activity to retinoic promote MDM2-independent p53 and phospho- for degradation. Proc Natl Acad Sci USA 106:11612– acid receptor ␣. Nat Genet 39:1500–1506. p53ser20 degradation. J Biol Chem 282:3273–3281.
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