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Trim24 targets endogenous p53 for degradation
Open accessAbstract
Numerous studies focus on the tumor suppressor p53 as a protector of genomic stability, mediator of cell cycle arrest and apoptosis, and target of mutation in 50% of all human cancers. The vast majority of information on p53, its protein-interaction partners and regulation, comes from studies of tumor-derived, cultured cells where p53 and its regulatory controls may be mutated or dysfunctional. To address regulation of endogenous p53 in normal cells, we created a mouse and stem cell model by knock-in (KI) of a tandem-affinity-purification (TAP) epitope at the endogenous Trp-53 locus. Mass spectrometry of TAP-purified p53-complexes from embryonic stem cells revealed Tripartite-motif protein 24 (Trim24), a previously unknown partner of p53. Mutation of TRIM24 homolog, bonus , in Drosophila led to apoptosis, which could be rescued by p53-depletion. These in vivo analyses establish TRIM24/bonus as a pathway that negatively regulates p53 in Drosophila . The Trim24-p53 link is evolutionarily conserved, as TRIM24 depletion in human breast cancer cells caused p53-dependent, spontaneous apoptosis. We found that Trim24 ubiquitylates and negatively regulates p53 levels, suggesting Trim24 as a therapeutic target to restore tumor suppression by p53.
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“TRIM24 can bind an acetylated peptide of the tumour suppressor p53, leading to ubiquitylation and degradation of the target 130 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [130]
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“Different members of the TIF1 family interact with distinct transcription factors; ligand activated nuclear receptors or p53 [TRIM24 (29, 30)], Krüppel-associated box domain-containing zinc finger proteins [TRIM28, (31)], and transforming growth factor (TGF)-β receptor-activated mothers against decapentaplegic (SMAD)…”
BackgroundExpanding PROTACtable genome universe of E3 ligases
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Self-citationTRIM family contribute to tumorigenesis, cancer development, and drug resistance
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“Trim24 was identified as a p53-binding partner in screens using TAP-tagged p53 as the bait protein (Allton et al. 2009).”
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“Interestingly, while TRIM24 was initially identified as a transcriptional co-regulator, it has been recently shown to ubiquitinate TP53 for degradation in breast cancer (49) and could play a similar role in melanoma.”
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TRIM24 is an oncogenic transcriptional co-activator of STAT3 in glioblastoma
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“TIF1a ubiquitinates p53, the tumor-suppressing gene [22], and activates other genes associated with tumor development and cellular proliferation [23].”
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“TRIM24 is a p53-interacting protein identified through the affinity purification of a TAPtagged p53, from mouse embryonic stem cells (Allton et al. 2009).”
BackgroundHistone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling through TRIM24 Binding
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“Flag-TRIM24 was a gift from Michelle Barton (Addgene plasmid # 28138) (17), pCIG-PIK3CA was a gift from Joseph Gleeson (Addgene plasmid # 73056) (18), and pLNCX-Myr-AKT was a gift from Joan Brugge (Addgene plasmid # 17245) (19).”
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“Recently, several other ubiquitin ligases have been identified that also regulate p53 stability and include COP1 (8), Pirh2 (9), ARF-BP1/Mule (10), and Trim24 (11), although their roles in vivo are less clear.”
BackgroundThe Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression
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Overexpression of TRIM24 Correlates with Tumor Progression in Non-Small Cell Lung Cancer
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“TRIM24 could ubiquitylate and negatively regulate p53 levels, which made TRIM24 a therapeutic target to restore tumor suppression by p53 [12].”
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TRIM52 plays an oncogenic role in ovarian cancer associated with NF-kB pathway
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“Although it is likely that TRIM24 has an E3 ubiquitin ligase activity via its RING-finger domain [49], we could not find enhanced ubiquitination of BRD7 by TRIM24 (data not shown).”
BackgroundRoles of ubiquitin signaling in transcription regulation
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“For RNA analysis 500 ng total RNA was treated with DNaseI and cDNA was synthesized as previously described (29), and amplified with human gene specific primers (Supplementary Table S8) with Power SYBR Green PCR Master Mix (Applied Biosystems).”
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“Tripartite motif-containing 24 (Trim24) contains a zinc binding motif, a coiled-coiled region, and a RING domain, which has been shown to act as an E3-ubiquitin ligase and target tumor suppressor p53 for degradation [66].”
BackgroundUncovering Ubiquitin and Ubiquitin-like Signaling Networks
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Prognostic Significance of TRIM24/TIF-1α Gene Expression in Breast Cancer
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“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).”
BackgroundBromodomains as therapeutic targets in cancer
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“Experimental evidence in murine models of hepatocellular carcinoma has suggested a tumour suppressor function for TRIM24 and TRIM33 and mechanistic insights have demonstrated a functional interaction between these factors and key regulatory proteins including p53 [71], SMAD transcription factors [72] and oestrogen rec…”
BackgroundTIF1 Proteins in Genome Stability and Cancer
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“[94] first revealed this interaction by mass spectrometry peptide analysis of tagged-p53 complexes in ESCs.”
BackgroundTRIM28 interacts with EZH2 and SWI/SNF to activate genes that promote mammosphere formation
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Self-citationKilling by Degradation: Regulation of Apoptosis by the Ubiquitin-Proteasome-System
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Self-citationThe Role of the Double Bromodomain-Containing BET Genes During Mammalian Spermatogenesis
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“…et al., 2008; Tae et al., 2011; Zeng et al., 2008; Zhou & Grummt, 2005), ubiquitin ligases (Agricola, Randall, Gaarenstroom, Dupont, & Hill, 2011; Allton et al., 2009), sumo ligases (Liang et al., 2011), and chromatin remodelers (Liu, Mulholland, Fu, & Zhao, 2006; Racki et al., 2009; Thompson,…”
TRIM8 modulates p53 activity to dictate cell cycle arrest
Caratozzolo, M. F., Micale, L., Turturo, M. G., Cornacchia, S., Fusco, C., Marzano, F., Augello, B., D’Erchia, A. M., Guerrini, L., Pesole, G., et al. (2012) · Cell Cycle · doi:10.4161/cc.11.3.19008 · Cited by 72
“Notably other TRIMs are involved in p53 regulation.(34) For instance, the RING domain of TRIM24 functions as an E3-ubiquitin ligase that targets p53 for degradation, and its depletion induces p53-dependent apoptosis.”
BackgroundThe translational values of TRIM family in pan-cancers: From functions and mechanisms to clinics
Zhao, G., Liu, C., Wen, X., Luan, G., Xie, L., & Guo, X. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107881 · Cited by 74
Cui, Z., Cao, W., Li, J., Song, X., Mao, L., & Chen, W. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063887 · Cited by 70
“It was reported that the three conserved motifs work together to degrade wild-type p53 protein by tagging it with ubiquitin [7,8].”
BackgroundRegulation of the p53 Family Proteins by the Ubiquitin Proteasomal Pathway
Bang, S., Kaur, S., & Kurokawa, M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms21010261 · Cited by 69
“TRIM 24 Metastatic HCC [104] Liver specific Tumor Suppressor [104] Oncogene in breast cancer [105–107] 2009 [108]”
BackgroundInfluentialOverexpression of TRIM24 Is Associated with the Onset and Progress of Human Hepatocellular Carcinoma
Liu, X., Huang, Y., Yang, D., Li, X., Liang, J., Lin, L., Zhang, M., Zhong, K., Liang, B., & Li, J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0085462 · Cited by 69
“Previous studies indicated that TRIM24 could directly ubiquitinate p53 and negatively regulate protein level of p53 in breast cell lines, implying its roles in proliferation and apoptosis [9].”
BackgroundRETRACTED ARTICLE: Regulation of TRIM24 by miR-511 modulates cell proliferation in gastric cancer
Fang, Z., Zhang, L., Liao, Q., Wang, Y., Yu, F., Miao, F., Xiang, X., & Xiong, J. (2017) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-017-0489-1 · Cited by 68
RetractedLacoursiere, R. E., Hadi, D., & Shaw, G. S. (2022) · Biomolecules · doi:10.3390/biom12030467 · Cited by 74
“For example, p53, a central protein in cell cycle control, is ubiquitinated by the E3 ligases MDM2 [12,13], MKRN1 [14], TRIM24 [15], MUL1 [16], and HRD1 [17].”
BackgroundChen, Y., Guo, Y., Yang, H., Shi, G., Xu, G., Shi, J., Yin, N., & Chen, D. (2015) · Oncotarget · doi:10.18632/oncotarget.4291 · Cited by 69
“TRIM24 ubiquitinates p53 both in vivo and in vitro via its RING domain [27].”
BackgroundZhang, B., Mehrotra, S., Ng, W. L., & Calvi, B. R. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004581 · Cited by 71
“It remains possible that another family of ubiquitin ligases mediate p53 degradation in endocycling cells [71,72].”
BackgroundRyu, Y. S., Lee, Y., Lee, K. W., Hwang, C. Y., Maeng, J., Kim, J., Seo, Y., You, K., Song, B., & Kwon, K. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.241893 · Cited by 67
Maslon, M. M., & Hupp, T. R. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.06.005 · Cited by 68
Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery
Pei, H., Peng, Y., Zhao, Q., & Chen, Y. (2019) · RSC Advances · doi:10.1039/c9ra03423d · Cited by 70
Yumimoto, K., Yamauchi, Y., & Nakayama, K. I. (2020) · Cancers · doi:10.3390/cancers12051249 · Cited by 65
“Many E3 ligases have been found to mediate the K48-linked (including Mouse double minute 2 homolog (MDM2) [211,212], PIRH2 [213], TRIM24 [214], CRL4 [215], CRL5 [216], synoviolin [217], constitutively photomorphogenic 1 (COP1) [218], Caspase 8/10-associated RING proteins (CARPs) [219], ARF-BP1 [220,221], WW domain-con…”
BackgroundShi, S., Wang, L., Han, D., Wu, J., Jiao, D., Zhang, K.-L., Chen, J., Li, Y., Yang, F., Zhang, J., et al. (2019) · Theranostics · doi:10.7150/thno.29884 · Cited by 63
“Furthermore, TRIM24 could function as an ubiquitin ligase and negatively regulate p53 expression through proteasome-mediated degradation [32].”
BackgroundTRIM69 inhibits cataractogenesis by negatively regulating p53
Rong, X., Rao, J., Li, D., Jing, Q., Lü, Y., & Ji, Y. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101157 · Cited by 61
Herquel, B., Ouararhni, K., & Davidson, I. (2011) · Transcription · doi:10.4161/trns.2.5.17725 · Cited by 61
Making sense of ubiquitin ligases that regulate p53
Jain, A. K., & Barton, M. C. (2010) · Cancer Biology & Therapy · doi:10.4161/cbt.10.7.13445 · Cited by 60
“We used mosaic deletion analysis in Drosophila to assess the outcome of bonus loss of function.(58) Bonus is the single Drosophila representative of the TIF1 sub-family of TRIM (RING/B-box/Coiled-coil or Tripartite Motif) proteins and closest in homology to TRIM24 among the TRIM24/28/33 members.”
MethodSelf-citationTRIM proteins in lung cancer: Mechanisms, biomarkers and therapeutic targets
Zhan, W., & Zhang, S. (2021) · Life Sciences · doi:10.1016/j.lfs.2020.118985 · Cited by 61
Functional Roles of Bromodomain Proteins in Cancer
Boyson, S. P., Gao, C., Quinn, K. M., Boyd, J. R., Paculová, H., Frietze, S. E., & Glass, K. C. (2021) · Cancers · doi:10.3390/cancers13143606 · Cited by 59
When the guardian sleeps: Reactivation of the p53 pathway in cancer
Merkel, O., Taylor, N., Prutsch, N., Staber, P. B., Moriggl, R., Turner, S. D., & Kenner, L. (2017) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2017.02.003 · Cited by 56
“identified non-MDM-targeting negative regulators of p53, including PIRH2, COP1 and TRIM24, also appear promising as small molecule inhibitors (Allton et al., 2009; Dornan et al., 2004; Leng et al., 2003).”
BackgroundKung, C.-P., Khaku, S., Jennis, M., Zhou, Y., & Murphy, M. E. (2014) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-14-0385 · Cited by 58
“TRIM24, TRIM28, TRIM29 (also known as ataxia-telangiectasia group D complementing, or ATDC) and TRIM39 all inhibit p53 activity by increasing p53 degradation and/or nuclear export, largely by controlling p53 ubiquitylation (39-42).”
Chang, Y., Chi, L.-H., Chang, W., Su, C., Lin, Y.-F., Chen, C.-L., Chen, M., Chang, P. M., Wu, A. T. H., & Hsiao, M. (2017) · Journal of Hematology & Oncology · doi:10.1186/s13045-016-0372-0 · Cited by 57
“Third, TRIM24 contains a RING domain and E3 ligase activity that degrades p53, which controls gene expression [19].”
BackgroundTumor suppressor p53 cross-talks with TRIM family proteins
Liu, J., Zhang, C., Wang, X., Hu, W., & Feng, Z. (2020) · Genes & Diseases · doi:10.1016/j.gendis.2020.07.003 · Cited by 57
“TRIM24, also known as transcription intermediary factor 1a (TIF1a), was the first reported TRIM protein that directly targetes p53.(95) TRIM24 binds to p53 and promotes its ubiquitination, leading to decreased p53 levels and transcriptional activity in a RING-dependent manner.”
BackgroundIdentification of new p53 target microRNAs by bioinformatics and functional analysis
Bisio, A., Sanctis, V. D., Vescovo, V. D., Denti, M. A., Jegga, A. G., Inga, A., & Ciribilli, Y. (2013) · BMC Cancer · doi:10.1186/1471-2407-13-552 · Cited by 56
TRIM24 promotes the aggression of gastric cancer via the Wnt/β-catenin signaling pathway
Fang, Z., Deng, J., Zhang, L., Xiang, X., Yu, F., Chen, J., Feng, M., & Xiong, J. (2017) · Oncology Letters · doi:10.3892/ol.2017.5604 · Cited by 55
“TRIM24 ubiquitinates and induces the protea-some-mediated degradation of p53 (11,12), and can also bind to chromatin and the estrogen receptor to activate target genes associated with cell proliferation and tumor development in breast cancer (13).”
Han, Y., Tian, H., Chen, P., & Lin, Q. (2017) · Oncotarget · doi:10.18632/oncotarget.15188 · Cited by 54
“com/oncotarget TRIM24 and TRIM59 negatively regulate p53 through its E3 ligase activity [18, 22].”
BackgroundRegulation of gene expression in human cancers by TRIM24
Appikonda, S., Thakkar, K. N., & Barton, M. C. (2016) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2016.05.001 · Cited by 54
Self-citationTRIM24 links glucose metabolism with transformation of human mammary epithelial cells
Pathiraja, T. N., Thakkar, K. N., Jiang, S., Stratton, S. A., Liu, Z., Gagea, M., Shi, X., Shah, P. K., Phan, L. M., Lee, M.-H., et al. (2014) · Oncogene · doi:10.1038/onc.2014.220 · Cited by 52
Self-citationRivlin, N., Katz, S., Doody, M., Sheffer, M., Horesh, S., Molchadsky, A., Koifman, G., Shetzer, Y., Goldfinger, N., Rotter, V., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1320428111 · Cited by 52
“TRIM24, which was shown to target p53 for degradation (20), was found in our data to bind both WT and Mut proteins, thus providing additional evidence for the stabilization ofMut p53 into the WT form.”
BackgroundUbiquitylation of p53 by the APC/C inhibitor Trim39
Zhang, L., Huang, N.-J., Chen, C., Tang, W., & Kornbluth, S. A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1212047110 · Cited by 51
“Moreover, several other E3 ligases, including another Trim family member, Trim24, are capable of promoting p53 degradation (23).”
BackgroundMichaelides, I. N., & Collie, G. W. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01882 · Cited by 51
Borlepawar, A., Rangrez, A. Y., Bernt, A., Christen, L., Sossalla, S. T., Frank, D., & Frey, N. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.752543 · Cited by 48
“Moreover, XIAP is also a direct target of TRIM32 (47), and both TRIM24/32 have a known link with p53 in other cell types (35, 48, 49).”
BackgroundAppikonda, S., Thakkar, K. N., Shah, P. K., Dent, S., Andersen, J. N., & Barton, M. C. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002233 · Cited by 48
“TRIM24 depletion was previously reported to negatively affect MCF7 cell proliferation (7, 27).”
BackgroundMethodSelf-citationTRIM65 negatively regulates p53 through ubiquitination
Li, Y., Ma, C., Zhou, T., Liu, Y., Sun, L., & Yu, Z. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.03.093 · Cited by 47
Homobivalent, Trivalent, and Covalent PROTACs: Emerging Strategies for Protein Degradation
Yan, J., Li, T., Miao, Z., Wang, P., Sheng, C., & Zhuang, C. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00728 · Cited by 46
Targeting TRIM Proteins: A Quest towards Drugging an Emerging Protein Class
D’Amico, F., Mukhopadhyay, R., Ovaa, H., & Mulder, M. P. C. (2021) · ChemBioChem · doi:10.1002/cbic.202000787 · Cited by 44
Metadata
- Authors
- Allton, K., Jain, A. K., Herz, H.-M., Tsai, W.-W., Jung, S. Y., Qin, J., Bergmann, A., Johnson, R. L., & Barton, M. C.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- The University of Texas Health Science Center at Houston (US)
- Baylor College of Medicine (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-07-14
- Volume
- 106
- Issue
- 28
- Pages
- 11612-11616
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2710642
- OpenAlex
- W2037942882
- Cited by
- 292
- References
- 40
- Citations by year
- 2026: 7 · 2025: 24 · 2024: 8 · 2023: 25 · 2022: 15 · 2021: 20 · 2020: 23 · 2019: 12 · 2018: 17 · 2017: 23 · 2016: 15 · 2015: 13 · 2014: 16 · 2013: 11 · 2012: 28
- FWCI
- 10.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM081627, P01GM081627, GM068016, R01GM068016)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- TRIM24, p53, protein degradation, ubiquitination, tumor suppressor regulation, Drosophila, embryonic stem cells, tandem affinity purification, tumor suppression, breast cancer, apoptosis
- MeSH terms
- Animals, Chromatography, Gel, Drosophila, Humans, Mutation, Mass Spectrometry, Immunoblotting, Tumor Suppressor Protein p53, Apoptosis, Drosophila Proteins, Ubiquitin-Protein Ligases, Cell Line, Tumor, Chromatin Immunoprecipitation, Mice, Ubiquitination, Gene Knock-In Techniques
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