HDM2 antagonist Nutlin-3 disrupts p73-HDM2 binding and enhances p73 function
Abstract
Nutlin-3, a small molecule inhibitor, activates p53 by disrupting p53-HDM2 association. In this study, we found that Nutlin-3 suppressed cell growth and induced apoptosis in the absence of wild-type p53, suggesting a p53-independent mechanism for Nutlin-3-induced cell death. Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death. Since HDM2, a key negative regulator of p53, also binds to and inhibits p73, we asked whether p73 could mediate Nutlin-3-induced apoptosis. We demonstrate that Nutlin-3 inhibits endogenous binding between the proapoptotic p73 isoform TAp73alpha and HDM2 in p53-null cells. Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis. p73 knockdown by siRNA results in rescue of Nutlin-3-treated cells, indicating that Nutlin-3-induced apoptosis is, at least in part, p73 dependent. In addition, Nutlin-3 treatment increases TAp73alpha protein levels with prolongation of p73 half-life. These results provide the first evidence that Nutlin-3 disrupts endogenous p73-HDM2 interaction and enhances the stability and proapoptotic activities of p73 and thus, provides a rationale for the use of Nutlin-3 in the large number of human tumors in which p53 is inactivated.
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Nutlin3a binds the N-terminal hydrophobic pocket of MDM2 and prevents MDM2 from interacting with p53 and other signal transducers such as p73α, E2F1, Rb, and HIF-1α.
“The MDM2 protein–protein interaction (PPI) inhibitor nutlin3a binds to the N-terminal hydrophobic pocket of MDM2 and blocks interaction of MDM2 with not only p53 but also a number of other key signal transducers, including p73α, E2F1, Rb, and HIF-1α”
From Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist (2017) · cites this paper as [22]
Dosing regimens that build on front-line chemotherapy for GBM are not well described.
“information on dosing regimens that build upon front-line chemotherapy for GBM is lacking.19,21,22,34,43,45”
From Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist (2017) · cites this paper as [22]
Nutlin-3a also inhibits binding of p73α, E2F1, and Hif-1α to the N-terminal hydrophobic pocket of Mdm2.
“Nutlin-3a also inhibits the binding of the p73 isoform p73α, as well as E2F1 and hypoxia inducible factor 1α (Hif-1α), to the N-terminal hydrophobic pocket of Mdm2 (11–13).”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [12]
Lau and colleagues showed that Nutlin-3a treatment inhibits p73α binding to Mdm2, leading to p73α-mediated induction of pro-apoptotic downstream targets and increased apoptosis in cells lacking wild-type p53.
“Lau and colleagues showed that when cells were treated with Nutlin-3a, the binding of p73α to Mdm2 was inhibited, leading to p73α-mediated induction of pro-apoptotic downstream targets and increased apoptosis in cells lacking wild-type p53 (12).”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [12]
p53 and p73α both interact with Mdm2 in the same N-terminal hydrophobic pocket.
“While p53 and p73α can both interact with Mdm2 in the same N-terminal hydrophobic pocket (12), Mdm2 does not ubiquitinate p73α (44–46).”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [12]
These data are consistent with prior reports that p73α can bind the Mdm2 promoter and increase Mdm2 gene expression.
“These data are consistent with previous reports indicating that p73α can directly bind to the Mdm2 promoter and increase Mdm2 gene expression (12, 47).”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [12]
Nutlin-3a blockade of Mdm2 binding to p73α increases the available p73α pool, allowing transcriptional activation of pro-apoptotic genes and apoptosis in mutant p53 and p53-null cells.
“Blockade of the binding of Mdm2 to p73α by Nutlin-3a increases the pool of p73α available to transcriptionally activate pro-apoptotic gene expression and promote apoptosis in mutant p53 and p53 null cells (12).”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [12]
Cites
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661 · see citing works
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., & Pavletich, N. P. (1996) · Science · doi:10.1126/science.274.5289.948 · Cited by 2,206 · see citing works
Role for the p53 homologue p73 in E2F-1-induced apoptosis
Irwin, M. S., Marín, M. C., Phillips, A. C., Seelan, R. S., Smith, D. I., Liu, W., Flores, E. R., Tsai, K. Y., Jacks, T., Vousden, K. H., et al. (2000) · Nature · doi:10.1038/35036614 · Cited by 710 · see citing works
Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy
Tovar, C., Rosinski, J., Filipovic, Z., Higgins, B., Kolinsky, K., Hilton, H., Zhao, X., Vu, B. T., Qing, W., Packman, K., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507493103 · Cited by 708 · see citing works
Inactivation of the p53 pathway in retinoblastoma
Laurie, N. A., Donovan, S. L., Shih, C.-S., Zhang, J., Mills, N., Fuller, C., Teunisse, A., Lam, S., Ramos, Y., Mohan, A., et al. (2006) · Nature · doi:10.1038/nature05194 · Cited by 595 · see citing works
AIS is an oncogene amplified in squamous cell carcinoma
Hibi, K., Trink, B., Patturajan, M., Westra, W. H., Caballero, O. L., Hill, D. E., Ratovitski, E. A., Jen, J., & Sidransky, D. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.10.5462 · Cited by 464 · see citing works
p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis
Rocco, J. W., Leong, C., Kuperwasser, N., DeYoung, M. P., & Ellisen, L. W. (2006) · Cancer Cell · doi:10.1016/j.ccr.2005.12.013 · Cited by 435 · see citing works
Chemosensitivity linked to p73 function
Irwin, M. S., Kondo, K., Marín, M. C., Cheng, L. S., Hahn, W. C., & Kaelin, W. G. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00078-3 · Cited by 406 · see citing works
Iwakuma, T., & Lozano, G. (2003) · PubMed · Cited by 390 · see citing works
MDM2 suppresses p73 function without promoting p73 degradation
Zeng, X., Chen, L., Jost, C. A., Maya, R., Keller, D., Wang, X., Kaelin, W. G., Oren, M., Chen, J., & Lu, H. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.5.3257 · Cited by 334 · see citing works
MDM2 Is a Negative Regulator of p21 , Independent of p53
Zhang, Z., Wang, H., Li, M., Agrawal, S., Chen, X., & Zhang, R. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312264200 · Cited by 253 · see citing works
Coll-Mulet, L., Iglesias‐Serret, D., Santidrián, A. F., Cosialls, A. M., de Frías, M., Castaño, E., Campàs, C., Barragán, M., de Sevilla, A. F., Domingo, A., et al. (2006) · Blood · doi:10.1182/blood-2005-08-3273 · Cited by 233 · see citing works
ASPP1 and ASPP2: Common Activators of p53 Family Members
Bergamaschi, D., Samuels, Y., Jin, B., Duraisingham, S., Crook, T., & Lü, X. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.3.1341-1350.2004 · Cited by 229 · see citing works
Mdm2 binds p73α without targeting degradation
Bálint, E., Bates, S., & Vousden, K. H. (1999) · Oncogene · doi:10.1038/sj.onc.1202781 · Cited by 212 · see citing works
Levels of HdmX expression dictate the sensitivity of normal and transformed cells to Nutlin-3
Patton, J. T., Mayo, L. D., Singhi, A. D., Gudkov, A. V., Stark, G. R., & Jackson, M. W. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3832 · Cited by 189 · see citing works
Comparative study of the p53-mdm2 and p53-MDMX interfaces
Böttger, V., Böttger, A., Garcia-Echeverria, C., Ramos, Y. F., van der Eb, A. J., Jochemsen, A. G., & Lane, D. P. (1999) · Oncogene · doi:10.1038/sj.onc.1202281 · Cited by 189 · see citing works
Dual-Site Regulation of MDM2 E3-Ubiquitin Ligase Activity
Wallace, M., Worrall, E. G., Pettersson, S., Hupp, T. R., & Ball, K. L. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.05.029 · Cited by 171 · see citing works
Ambrosini, G., Sambol, E. B., Carvajal, D., Vassilev, L. T., Singer, S., & Schwartz, G. K. (2007) · Oncogene · doi:10.1038/sj.onc.1210136 · Cited by 163 · see citing works
Small-Molecule MDM2 Antagonists as a New Therapy Concept for Neuroblastoma
Maerken, T. V., Speleman, F., Vermeulen, J., Lambertz, I., Clercq, S. D., Smet, E. D., Yigit, N., Coppens, V., Philippé, J., Paepe, A. D., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0792 · Cited by 154 · see citing works
MDM2 and MDMX bind and stabilize the p53-related protein p73
Ongkeko, W. M., Wang, X. Q., Siu, W. Y., Lau, A. W. S., Yamashita, K., Harris, A. L., Cox, L. S., & Poon, R. Y. C. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80367-4 · Cited by 132 · see citing works
Mdm2-mediated NEDD8 Modification of TAp73 Regulates Its Transactivation Function
Watson, I. R., Blanch, A., Lin, D. C. C., Ohh, M., & Irwin, M. S. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m603654200 · Cited by 120 · see citing works
Shimizu, H., Burch, L. R., Smith, A. J., Dornan, D., Wallace, M., Ball, K. L., & Hupp, T. R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202296200 · Cited by 116 · see citing works
MDM2 and MDMX can interact differently with ARF and members of the p53 family
Wang, X., Arooz, T., Siu, W. Y., Chiu, C. H. S., Lau, A., Yamashita, K., & Poon, R. Y. C. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)02124-x · Cited by 94 · see citing works
Calabrò, V., Mansueto, G., Parisi, T., Vivo, M., Calogero, R., & Mantia, G. L. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m107173200 · Cited by 94 · see citing works
LaRusch, G. A., Jackson, M. W., Dunbar, J. D., Warren, R. S., Donner, D. B., & Mayo, L. D. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-2710 · Cited by 89 · see citing works
Binding of p53 to the Central Domain of Mdm2 Is Regulated by Phosphorylation
Kulikov, R., Winter, M., & Blattner, C. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m513311200 · Cited by 79 · see citing works
Regulation of p63 Function by Mdm2 and MdmX
Kadakia, M., Slader, C., & Berberich, S. J. (2001) · DNA and Cell Biology · doi:10.1089/10445490152122433 · Cited by 73 · see citing works
A Second p53 Binding Site in the Central Domain of Mdm2 Is Essential for p53 Ubiquitination
Ma, J., Martin, J. D., Zhang, H., Auger, K. R., Ho, T. F., Kirkpatrick, R. B., Grooms, M. H., Johanson, K., Tummino, P. J., Copeland, A. R. A., et al. (2006) · Biochemistry · doi:10.1021/bi060661u · Cited by 68 · see citing works
Family Feud in Chemosensitvity: p73 and Mutant p53
Irwin, M. S. (2004) · Cell Cycle · doi:10.4161/cc.3.3.768 · Cited by 63 · see citing works
VanderBorght, A., Valckx, A., Dun, J. V., Grand‐Perret, T., Schepper, S. D., Vialard, J., Janicot, M., & Arts, J. (2006) · Oncogene · doi:10.1038/sj.onc.1209667 · Cited by 27 · see citing works
Flagged first, then by citations
1 of the 31 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
The role of p53 in cancer drug resistance and targeted chemotherapy
Hientz, K., Mohr, A., Bhakta-Guha, D., & Efferth, T. (2016) · Oncotarget · doi:10.18632/oncotarget.13475 · Cited by 590 · see citing works
Dutt, S., Narla, A., Lin, K. I., Mullally, A., Abayasekara, N., Megerdichian, C., Wilson, F. H., Currie, T., Khanna‐Gupta, A., Berliner, N., et al. (2010) · Blood · doi:10.1182/blood-2010-07-295238 · Cited by 410 · see citing works
Translating p53 into the clinic
Cheok, C. F., Verma, C. S., Baselga, J., & Lane, D. P. (2011) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2010.174 · Cited by 381 · see citing works
Targeting the MDM2-p53 Interaction for Cancer Therapy
Shangary, S. K., & Wang, S. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-5136 · Cited by 364 · see citing works
p53 Family and Cellular Stress Responses in Cancer
Pflaum, J., Schlosser, S., & ller, M. M. ⁄. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00285 · Cited by 294 · see citing works
Noxa: at the tip of the balance between life and death
Ploner, C., Kofler, R., & Villunger, A. (2008) · Oncogene · doi:10.1038/onc.2009.46 · Cited by 286 · see citing works
Tisato, V., Voltan, R., Gonelli, A., Secchiero, P., & Zauli, G. (2017) · Journal of Hematology & Oncology · doi:10.1186/s13045-017-0500-5 · Cited by 255 · see citing works
Targeting p53 for Novel Anticancer Therapy
Wang, Z., & Sun, Y. (2010) · Translational Oncology · doi:10.1593/tlo.09250 · Cited by 249 · see citing works
p53-based Cancer TherapyPreprint
Lane, D. P., Cheok, C. F., & Laı́n, S. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001222 · Cited by 244 · see citing works
Marti, P., Stein, C., Blumer, T., Abraham, Y., Dill, M. T., Pikiolek, M., Orsini, V., Jurisic, G., Megel, P., Makowska, Z., et al. (2015) · Hepatology · doi:10.1002/hep.27992 · Cited by 232 · see citing works
Tumour suppression by p53: the importance of apoptosis and cellular senescence
Zuckerman, V., Wolyniec, K., Sionov, R. V., Haupt, S., & Haupt, Y. (2009) · The Journal of Pathology · doi:10.1002/path.2584 · Cited by 210 · see citing works
Targeting the p53 signaling pathway in cancer therapy – the promises, challenges and perils
Stegh, A. H. (2012) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2011.643299 · Cited by 192 · see citing works
Current developments of targeting the p53 signaling pathway for cancer treatment
Huang, J. L. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107720 · Cited by 155 · see citing works
Pharmacologic Activation of p53 by Small-Molecule MDM2 Antagonists
Shen, H., & Maki, C. G. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211795222603 · Cited by 143 · see citing works
Rufini, A., Agostini, M., Grespi, F., Tomasini, R., Sayan, B. S., Niklison-Chirou, M. V., Conforti, F., Velletri, T., Mastino, A., Mak, T. W., et al. (2011) · Genes & Cancer · doi:10.1177/1947601911408890 · Cited by 138 · see citing works
Effect of low doses of actinomycin D on neuroblastoma cell lines
Cortes, C. L., Veiga, S. R., Almacellas, E., Hernández‐Losa, J., Ferreres, J. C., Kozma, S. C., Ambrosio, S., Thomas, G., & Tauler, A. (2016) · Molecular Cancer · doi:10.1186/s12943-015-0489-8 · Cited by 132 · see citing works
The roles and regulation of MDM2 and MDMX: it is not just about p53Preprint
Klein, A. M., de Queiroz, R. M., Venkatesh, D., & Prives, C. L. (2021) · Genes & Development · doi:10.1101/gad.347872.120 · Cited by 132 · see citing works
Thomasová, D., Mulay, S. R., Bruns, H., & Anders, H. (2012) · Neoplasia · doi:10.1593/neo.121534 · Cited by 126 · see citing works
Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP
Yuan, Y., Liao, Y.-M., Hsueh, C.-T., & Mirshahidi, H. (2011) · Journal of Hematology & Oncology · doi:10.1186/1756-8722-4-16 · Cited by 118 · see citing works
Targeting p53 by small molecules in hematological malignancies
Saha, M. N., Qiu, L., & Chang, H. H. (2013) · Journal of Hematology & Oncology · doi:10.1186/1756-8722-6-23 · Cited by 112 · see citing works
Das, M., Duan, W., & Sahoo, S. K. (2014) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2014.09.002 · Cited by 111 · see citing works
Targeting the p53-MDM2 pathway for neuroblastoma therapy: Rays of hope
Zafar, A., Wang, W., Liu, G., Xian, W., McKeon, F., Zhou, J., & Zhang, R. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.09.023 · Cited by 107 · see citing works
Discovery of Mdm2-MdmX E3 Ligase Inhibitors Using a Cell-Based Ubiquitination Assay
Herman, A. G., Hayano, M., Poyurovsky, M. V., Shimada, K., Skouta, R., Prives, C., & Stockwell, B. R. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0104 · Cited by 100 · see citing works
Ray, R. M., Bhattacharya, S., & Johnson, L. R. (2010) · APOPTOSIS · doi:10.1007/s10495-010-0538-0 · Cited by 100 · see citing works
Preeclampsia Is Associated with Alterations in the p53-Pathway in Villous Trophoblast
Sharp, A. N., Heazell, A. E. P., Baczyk, D., Dunk, C., Lacey, H. A., Jones, C. J. P., Perkins, J., Kingdom, J. C., Baker, P. N., & Crocker, I. P. (2014) · PLoS ONE · doi:10.1371/journal.pone.0087621 · Cited by 98 · see citing works
PRIMA-1Met/APR-246 Displays High Antitumor Activity in Multiple Myeloma By Induction of p73 and Noxa
Saha, M. N., Jiang, H., Yang, Y., Reece, D. E., & Chang, H. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-1166 · Cited by 99 · see citing works
Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy
Song, B., Yang, P., & Zhang, S. (2024) · 癌症：英文版 · doi:10.1002/cac2.12520 · Cited by 97 · see citing works
Roh, J., Kang, S. K., Minn, I., Califano, J. A., Sidransky, D., & Koch, W. M. (2010) · Oral Oncology · doi:10.1016/j.oraloncology.2010.10.011 · Cited by 93 · see citing works
CRISPR-Cas9–based target validation for p53-reactivating model compounds
Wanzel, M., Vischedyk, J. B., Gittler, M. P., Gremke, N., Seiz, J. R., Hefter, M., Noack, M., Savai, R., Mernberger, M., Charles, J. P., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1965 · Cited by 87 · see citing works
BH3-Only Proteins Noxa and Puma Are Key Regulators of Induced Apoptosis
Roufayel, R., Younes, K., Al-Sabi, A., & Murshid, N. (2022) · Life · doi:10.3390/life12020256 · Cited by 88 · see citing works
Kitagawa, M., Aonuma, M., Lee, S. H., Fukutake, S., & McCormick, F. P. (2008) · Oncogene · doi:10.1038/onc.2008.164 · Cited by 88 · see citing works
Arnhold, V., Schmelz, K., Proba, J., Winkler, A., Wünschel, J., Toedling, J., Deubzer, H. E., Künkele, A., Eggert, A., Schulte, J. H., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.23409 · Cited by 85 · see citing works
Tabe, Y., Sebasigari, D., Jin, L., Rudelius, M., Davies-Hill, T., Miyake, K., Miida, T., Pittaluga, S., & Raffeld, M. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0399 · Cited by 83 · see citing works
McCormack, E., Haaland, I., Venås, G., Forthun, R. B., Huseby, S., Gausdal, G., Knappskog, S., Micklem, D., Lorens, J. B., Bruserud, Ø., et al. (2011) · Leukemia · doi:10.1038/leu.2011.315 · Cited by 82 · see citing works
Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors
LaPlante, G., & Zhang, W. (2021) · Cancers · doi:10.3390/cancers13123079 · Cited by 82 · see citing works
Rastogi, S., Rizwani, W., Joshi, B., Kunigal, S., & Chellappan, S. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.93 · Cited by 82 · see citing works
MDM2 antagonist Nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines
Ohnstad, H. O., Paulsen, E. B., Noordhuis, P., Berg, M., Lothe, R. A., Vassilev, L. T., & Myklebost, O. (2011) · BMC Cancer · doi:10.1186/1471-2407-11-211 · Cited by 78 · see citing works
Lakoma, A., Barbieri, E., Agarwal, S., Jackson, J. R., Chen, Z., Kim, Y., McVay, M. C., Shohet, J. M., & Kim, E. S. (2015) · Cell Death Discovery · doi:10.1038/cddiscovery.2015.26 · Cited by 77 · see citing works
Deben, C., Wouters, A., de Beeck, K. O., van Den Bossche, J., Jacobs, J., Zwaenepoel, K., Peeters, M., Van Meerbeeck, J., Lardon, F., Rolfo, C., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.4433 · Cited by 73 · see citing works
Polo-Like Kinase 1 Depletion Induces DNA Damage in Early S Prior to Caspase Activation
Yim, H., & Erikson, R. L. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01277-08 · Cited by 73 · see citing works
Targeting the MDM2-p53 protein–protein interaction for new cancer therapeutics
Wang, S., Zhao, Y., Bernard, D., Aguilar, A., & Kumar, S. (2012) · Topics in Medicinal Chemistry · doi:10.1007/978-3-642-28965-1_2 · Cited by 72 · see citing works
Dithiocarbamate-inspired side chain stapling chemistry for peptide drug design
Li, X., Tolbert, W. D., Hu, H., Gohain, N., Zou, Y., Niu, F., He, W., Yuan, W., Su, J., Pazgier, M., et al. (2018) · Chemical Science · doi:10.1039/c8sc03275k · Cited by 71 · see citing works
Zhang, L., McGraw, K. L., Sallman, D. A., & List, A. F. (2016) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2016.1266625 · Cited by 67 · see citing works
Azmi, A. S., Aboukameel, A., Banerjee, S., Wang, Z., Mohammad, M., Wu, J., Wang, S., Yang, D., Philip, P. A., Sarkar, F. H., et al. (2010) · European Journal of Cancer · doi:10.1016/j.ejca.2010.01.015 · Cited by 67 · see citing works
Drakos, E., Singh, R. R., Rassidakis, G. Z., Schlette, E. J., Li, J., Claret, F. X., Ford, R. J., Vega, F., & Medeiros, L. J. (2011) · Leukemia · doi:10.1038/leu.2011.28 · Cited by 67 · see citing works
Peirce (2009) · International Journal of Oncology · doi:10.3892/ijo_00000267 · Cited by 67 · see citing works
Hároníková, L., Bonczek, O., Zatloukalová, P., Kokas, F. Z., Kucerikova, M., Coates, P. J., Fåhræus, R., & Vojtěšek, B. (2021) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-021-00293-6 · Cited by 71 · see citing works
Murine double minute 2: p53-independent roads lead to genome instability or death
Bouska, A. C., & Eischen, C. M. (2009) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2009.02.006 · Cited by 65 · see citing works
New strategies in soft tissue sarcoma treatment
Ceruso, M. S., El-Ghazzi, N., & Italiano, A. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01580-3 · Cited by 67 · see citing works
Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma
Traweek, R. S., Cope, B. M., Roland, C. L., Keung, E. Z.-Y., Nassif, E. F., & Erstad, D. J. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1006959 · Cited by 61 · see citing works
Zheng, T., Yin, D., Lu, Z., Wang, J., Li, Y., Chen, X., Liang, Y., Song, X., Qi, S., Sun, B., et al. (2014) · Molecular Cancer · doi:10.1186/1476-4598-13-133 · Cited by 60 · see citing works
Neuroblastoma: oncogenic mechanisms and therapeutic exploitation of necroptosis
Nicolai, S., Pieraccioli, M., Peschiaroli, A., Melino, G., & Raschellà, G. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.354 · Cited by 59 · see citing works
Mdm2 Is Required for Survival and Growth of p53-Deficient Cancer Cells
Feeley, K. P., Adams, C. M., Mitra, R., & Eischen, C. M. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-0809 · Cited by 57 · see citing works
p53 stabilization induces apoptosis in chronic myeloid leukemia blast crisis cells
Peterson, L. F., Mitrikeska, E., Giannola, D. M., Lui, Y., Sun, H., Bixby, D. L., Malek, S. N., Donato, N. J., Wang, S., & Talpaz, M. (2011) · Leukemia · doi:10.1038/leu.2011.7 · Cited by 55 · see citing works
Mdm2 and MdmX as Regulators of Gene Expression
Biderman, L., Manley, J. L., & Prives, C. L. (2012) · Genes & Cancer · doi:10.1177/1947601912455331 · Cited by 55 · see citing works
p53 Modulation as a Therapeutic Strategy in Gastrointestinal Stromal Tumors
Henze, J., Mühlenberg, T., Simon, S., Grabellus, F., Rubin, B. P., Taeger, G., Schüler, M., Treckmann, J. W., Dêbiec‐Rychter, M., Taguchi, T., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037776 · Cited by 54 · see citing works
The p53 Family Protein p73 Provides New Insights into Cancer Chemosensitivity and Targeting
Lunghi, P., Costanzo, A., Mazzera, L., Rizzoli, V., Levrero, M., & Bonati, A. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1229 · Cited by 54 · see citing works
Therapeutic prospects for p73 and p63: Rising from the shadow of p53
Vilgelm, A. E., El-Rifai, W. M., & Zaika, A. I. (2008) · Drug Resistance Updates · doi:10.1016/j.drup.2008.08.001 · Cited by 53 · see citing works
Nutlin-3 enhances the bortezomib sensitivity of p53-defective cancer cells by inducing paraptosis
Lee, D. M., Kim, I. Y., Seo, M. J., Kwon, M. R., & Choi, K. S. (2017) · Experimental & Molecular Medicine · doi:10.1038/emm.2017.112 · Cited by 52 · see citing works
Targeting the ubiquitin–proteasome system to activate wild-type p53 for cancer therapy
Allende-Vega, N., & Saville, M. K. (2009) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2009.10.004 · Cited by 51 · see citing works
Zheng, T., Wang, J., Song, X., Meng, X., Pan, S., Jiang, H., & Liu, L. (2010) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-010-0817-8 · Cited by 51 · see citing works
MDM2 Inhibitor Nutlin-3a Induces Apoptosis and Senescence in Cutaneous T-Cell Lymphoma: Role of p53
Manfé, V., Biskup, E., Johansen, P., Kamstrup, M. R., Krejsgaard, T., Morling, N., Wulf, H. C., & Gniadecki, R. (2012) · Journal of Investigative Dermatology · doi:10.1038/jid.2012.10 · Cited by 50 · see citing works
Wang, H., Cai, S., Bailey, B. J., Reza Saadatzadeh, M., Ding, J., Tonsing-Carter, E., Georgiadis, T. M., Zachary Gunter, T., Long, E. C., Minto, R. E., et al. (2017) · Journal of Neurosurgery · doi:10.3171/2016.1.jns152513 · Cited by 49 · see citing works
MDM2, MDMX, and p73 regulate cell-cycle progression in the absence of wild-type p53
Klein, A. M., Biderman, L., Tong, D., Alaghebandan, B., Plumber, S. A., Mueller, H. S., van Vlimmeren, A. E., Katz, C., & Prives, C. L. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2102420118 · Cited by 47 · see citing works
Lai, C.-Y., Tsai, A.-C., Chen, M.-C., Chang, L.-H., Sun, H., Chang, Y.-L., Chen, C.-C., Teng, C., & Pan, S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042192 · Cited by 49 · see citing works
Nutlins and Ionizing Radiation in Cancer Therapy
Impicciatore, G. G., Sancilio, S., Miscia, S., & Pietro, R. D. (2010) · Current Pharmaceutical Design · doi:10.2174/138161210791033932 · Cited by 49 · see citing works
Pharmacologic activation of wild-type p53 by nutlin therapy in childhood cancer
Maerken, T. V., Rihani, A., Goethem, A. V., Paepe, A. D., Speleman, F., & Vandesompele, J. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.11.002 · Cited by 47 · see citing works
MDM2-p53 Interaction in Paediatric Solid Tumours: Preclinical Rationale, Biomarkers and Resistance
Barone, G., Tweddle, D. A., Shohet, J. M., Chesler, L., Moreno, L., Pearson, A. D. J., & Maerken, T. V. (2014) · Current Drug Targets · doi:10.2174/13894501113149990194 · Cited by 45 · see citing works
Das, R., Bhattacharya, K., Sarkar, S., Samanta, S. K., Pal, B. C., & Mandal, C. (2013) · APOPTOSIS · doi:10.1007/s10495-013-0907-6 · Cited by 45 · see citing works
RetractedLin, H., Wang, L., Liu, Z., Long, K., Kong, M., Ye, D., Chen, X., Wang, K., Wu, K. K., Fan, M., et al. (2022) · Advanced Science · doi:10.1002/advs.202200742 · Cited by 43 · see citing works
Drakos, E., Atsaves, V., Schlette, E. J., Li, J.-D., Papanastasi, E., Rassidakis, G. Z., & Medeiros, L. J. (2009) · Leukemia · doi:10.1038/leu.2009.180 · Cited by 44 · see citing works
Anticancer effects of the p53 activator nutlin-3 in Ewing’s sarcoma cells
Sonnemann, J., Palani, C. D., Wittig, S., Becker, S., Eichhorn, F., Voigt, A., & Beck, J. F. (2011) · European Journal of Cancer · doi:10.1016/j.ejca.2011.01.015 · Cited by 43 · see citing works
Structurally diverse MDM2–p53 antagonists act as modulators of MDR-1 function in neuroblastoma
Chen, L., Zhao, Y., Halliday, G. C., Berry, P., Rousseau, R. F., Middleton, S. A., NICHOLS, G. L., Bello, F. D., Piergentili, A., Newell, D. R., et al. (2014) · British Journal of Cancer · doi:10.1038/bjc.2014.325 · Cited by 43 · see citing works
p53, SKP2, and DKK3 as MYCN Target Genes and Their Potential Therapeutic Significance
Chen, L., & Tweddle, D. A. (2012) · Frontiers in Oncology · doi:10.3389/fonc.2012.00173 · Cited by 43 · see citing works
Dabiri, Y., el Maaty, M. A. A., Chan, H. Y., Wölker, J., Ott, I., Wölfl, S., & Cheng, X. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00438 · Cited by 43 · see citing works
Tonsing-Carter, E., Bailey, B. J., Saadatzadeh, M. R., Ding, J., Wang, H., Sinn, A. L., Peterman, K. M., Spragins, T. K., Silver, J. M., Sprouse, A. A., et al. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0237 · Cited by 42 · see citing works
MDM2 mediates p73 ubiquitination: a new molecular mechanism for suppression of p73 function
Wu, H., & Leng, R. P. (2015) · Oncotarget · doi:10.18632/oncotarget.4086 · Cited by 41 · see citing works
Resurrecting a p53 peptide activator - An enabling nanoengineering strategy for peptide therapeutics
He, W., Yan, J., Li, Y., Yan, S., Wang, S., Hou, P., & Lu, W. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.06.041 · Cited by 42 · see citing works
Lago, S., Nadai, M., Ruggiero, E., Tassinari, M., Marušič, M., Tosoni, B., Frasson, I., Cernilogar, F. M., Pirota, V., Doria, F., et al. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa1273 · Cited by 41 · see citing works
The Role of MDM2 in Promoting Genome Stability versus Instability
Saadatzadeh, M. R., Elmi, A. N., Pandya, P. H., Bijangi‐Vishehsaraei, K., Ding, J., Stamatkin, C. W., Cohen‐Gadol, A., & Pollok, K. E. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102216 · Cited by 43 · see citing works
Maas, A.-M., Bretz, A. C., Mack, E., & Stiewe, T. (2011) · Cancer Letters · doi:10.1016/j.canlet.2011.07.030 · Cited by 40 · see citing works
Gomes, S., Raimundo, L., Soares, J., Loureiro, J. B., Leão, M., Ramos, H., Monteiro, M. N., Lemos, A., Moreira, J., Pinto, M. M. M., et al. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.01.014 · Cited by 39 · see citing works
p73 as a Pharmaceutical Target for Cancer Therapy
Bisso, A., Collavin, L., & Sal, G. D. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211795222667 · Cited by 38 · see citing works
Santag, S., Jäger, W., Karsten, C. B., Kati, S., Pietrek, M., Steinemann, D., Sarek, G., Ojala, P. M., & Schulz, T. F. (2012) · Oncogene · doi:10.1038/onc.2012.385 · Cited by 36 · see citing works
Haaland, I., Opsahl, J. A., Berven, F. S., Reikvam, H., Fredly, H., Haugse, R., Thiede, B., McCormack, E., Laı́n, S., Bruserud, Ø., et al. (2014) · Molecular Cancer · doi:10.1186/1476-4598-13-116 · Cited by 36 · see citing works
JNK–NQO1 axis drives TAp73-mediated tumor suppression upon oxidative and proteasomal stress
Kostecka, A., Sznarkowska, A., Meller, K., Acedo, P., Shi, Y., Sakil, H. A. M., Kawiak, A., Lion, M., Królicka, A., Wilhelm, M., et al. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.408 · Cited by 35 · see citing works
Regulatory feedback loop between TP73 and TRIM32
González-Cano, L., Hillje, A., Fuertes-Álvarez, S., Marqués, M. M., Blanch, A., Ian, R. W., Irwin, M. S., Schwamborn, J. C., & Marín, M. C. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.224 · Cited by 34 · see citing works
The yeast two-hybrid system and its role in drug discovery
Lentze, N., & Auerbach, D. (2008) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.12.4.505 · Cited by 34 · see citing works
Nutlin-3 Affects Expression and Function of Retinoblastoma Protein
Du, W., Wu, J., Walsh, E. M., Zhang, Y., Chen, C. Y., & Xiao, Z.-X. J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.046904 · Cited by 33 · see citing works
iASPP Inhibition: Increased Options in Targeting the p53 Family for Cancer Therapy
Bell, H. S., & Ryan, K. M. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0182 · Cited by 33 · see citing works
Cyclooxygenase inhibitors differentially modulate p73 isoforms in neuroblastoma
Lau, L. M. S., Wolter, J. K., Lau, J. T. M. L., Cheng, L. S., Smith, K. M., Hansford, L. M., Zhang, L., Baruchel, S., Robinson, F., & Irwin, M. S. (2009) · Oncogene · doi:10.1038/onc.2009.59 · Cited by 33 · see citing works
Jones, R. J., Chen, Q., Voorhees, P. M., Young, K. H., Bruey-Sédano, N., Yang, D., & Orlowski, R. Z. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0150 · Cited by 30 · see citing works
Carrillo, A. M., Hicks, M., Khabele, D., & Eischen, C. M. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0089 · Cited by 31 · see citing works
p73: From the p53 shadow to a major pharmacological target in anticancer therapy
Ramos, H., Raimundo, L., & Saraiva, L. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105245 · Cited by 31 · see citing works
Resistance acquisition to MDM2 inhibitors
Cinatl, J., Speidel, D., Hardcastle, I., & Michaelis, M. (2014) · Biochemical Society Transactions · doi:10.1042/bst20140035 · Cited by 30 · see citing works
Novel p53 therapies for head and neck cancer
Castellanos, M. R., & Pan, Q. (2016) · World Journal of Otorhinolaryngology - Head and Neck Surgery · doi:10.1016/j.wjorl.2016.05.005 · Cited by 29 · see citing works
Zanjirband, M., & Rahgozar, S. (2019) · Current Drug Targets · doi:10.2174/1389450120666190402120701 · Cited by 29 · see citing works
Renouf, B., Hollville, É., Pujals, A., Tétaud, C., Garibal, J., & Wiels, J. (2009) · Leukemia · doi:10.1038/leu.2009.92 · Cited by 29 · see citing works
Dey, A., Lane, D. P., & Verma, C. S. (2010) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2010.02.004 · Cited by 27 · see citing works
Carstens, M. R., Fisher, R. C., Acharya, A. P., Butterworth, E. A., Scott, E. W., Huang, E. H., & Keselowsky, B. G. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1505374112 · Cited by 27 · see citing works
- Authors
- Lau, L. M. S., Nugent, J. K., Zhao, X., & Irwin, M. S.
- Affiliations
- University of Toronto (CA)
- Corresponding author
- Irwin, M S
- Venue
- Oncogene
- Published
- 2007-08-13
- Volume
- 27
- Issue
- 7
- Pages
- 997-1003
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2029865335
- Cited by
- 182
- References
- 31
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 5 · 2023: 2 · 2022: 10 · 2021: 7 · 2020: 10 · 2019: 8 · 2018: 5 · 2017: 6 · 2016: 9 · 2015: 11 · 2014: 15 · 2013: 6 · 2012: 18
- FWCI
- 6.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canada Research Chairs
- Terry Fox Foundation
- Hospital for Sick Children
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- Nutlin-3, p73, MDM2, p53-independent apoptosis, Noxa, PUMA, p21, transcriptional activation, p53-null cells, p53 inactivation, cancer therapy
- MeSH terms
- Bone Neoplasms, DNA-Binding Proteins, Humans, Imidazoles, Nuclear Proteins, Piperazines, Protein Binding, Proto-Oncogene Proteins, Osteosarcoma, Transcription, Genetic, Protein Biosynthesis, Immunoblotting, Tumor Suppressor Protein p53, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Tumor Suppressor Proteins, RNA, Small Interfering, HCT116 Cells, Immunoprecipitation, Cyclin-Dependent Kinase Inhibitor p21, Apoptosis Regulatory Proteins, Proto-Oncogene Proteins c-mdm2
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