Cooperation of Nutlin-3a and a Wip1 inhibitor to induce p53 activity
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// Anusha Sriraman 1 , Marija Radovanovic 1 , Magdalena Wienken 1 , Zeynab Najafova 2 , Yizhu Li 1 and Matthias Dobbelstein 1 1 Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen, Germany 2 Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany Correspondence to: Yizhu Li, email: // Matthias Dobbelstein, email: // Keywords : Mdm2, Wip1/PPM1D, p53, kinase, phosphatase Received : February 13, 2016 Accepted : April 26, 2016 Published : May 11, 2016 Abstract Targeting the Mdm2 oncoprotein by drugs has the potential of re-establishing p53 function and tumor suppression. However, Mdm2-antagonizing drug candidates, e. g. Nutlin-3a, often fail to abolish cancer cell growth sustainably. To overcome these limitations, we inhibited Mdm2 and simultaneously a second negative regulator of p53, the phosphatase Wip1/PPM1D. When combining Nutlin-3a with the Wip1 inhibitor GSK2830371 in the treatment of p53-proficient but not p53-deficient cells, we observed enhanced phosphorylation (Ser 15) and acetylation (Lys 382) of p53, increased expression of p53 target gene products, and synergistic inhibition of cell proliferation. Surprisingly, when testing the two compounds individually, largely distinct sets of genes were induced, as revealed by deep sequencing analysis of RNA. In contrast, the combination of both drugs led to an expression signature that largely comprised that of Nutlin-3a alone. Moreover, the combination of drugs, or the combination of Nutlin-3a with Wip1-depletion by siRNA, activated p53-responsive genes to a greater extent than either of the compounds alone. Simultaneous inhibition of Mdm2 and Wip1 enhanced cell senescence and G2/M accumulation. Taken together, the inhibition of Wip1 might fortify p53-mediated tumor suppression by Mdm2 antagonists.
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When combined with MDM2 inhibitors, both stability and activity of p53 are increased, leading to pronounced cell death.
“When this is combined with MDM2 inhibitors, both stability and activity of p53 are increased, leading to pronounced cell death.”
From CDK4 inhibition diminishes p53 activation by MDM2 antagonists (2018) · cites this paper as [19]
PPM1D/Wip1 might represent a suitable target of drugs that synergize with MDM2 antagonists.
“Our previous work suggests that the phosphatase PPM1D/Wip1 might represent a suitable target of drugs that synergize with MDM2 antagonists19,45.”
From CDK4 inhibition diminishes p53 activation by MDM2 antagonists (2018) · cites this paper as [19]
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Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106 · see citing works
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849 · see citing works
HTSeq—a Python framework to work with high-throughput sequencing data
Anders, S., Pyl, P. T., & Huber, W. (2015) · Bioinformatics · doi:10.1093/bioinformatics/btu638 · Cited by 21,464 · see citing works
Model-based Analysis of ChIP-Seq (MACS)
Zhang, Y., Liu, T., Meyer, C. A., Eeckhoute, J., Johnson, D. S., Bernstein, B. E., Nusbaum, C., Myers, R. M., Brown, M., Li, W., et al. (2008) · Genome Biology · doi:10.1186/gb-2008-9-9-r137 · Cited by 18,386 · see citing works
Kim, D., Pertea, G., Trapnell, C., Pimentel, H., Kelley, R., & Salzberg, S. L. (2013) · Genome Biology · doi:10.1186/gb-2013-14-4-r36 · Cited by 12,668 · see citing works
Mootha, V. K., Lindgren, C. M., Eriksson, K.-F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstråle, M., Laurila, E., et al. (2003) · Nature Genetics · doi:10.1038/ng1180 · Cited by 10,197 · see citing works
Drug combination studies and their synergy quantification using the Chou-Talalay method
Chou, T.-C. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-1947 · Cited by 5,739 · see citing works
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
deepTools: a flexible platform for exploring deep-sequencing data
Ramírez, F., Dündar, F., Diehl, S., Grüning, B. A., & Manke, T. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku365 · Cited by 3,738 · see citing works
Requirement for p53 and p21 to Sustain G <sub>2</sub> Arrest After DNA Damage
Bunz, F., Dutriaux, A., Lengauer, C., Waldman, T., Zhou, S., Brown, J. P., Sedivy, J. M., Kinzler, K. W., & Vogelstein, B. (1998) · Science · doi:10.1126/science.282.5393.1497 · Cited by 2,803 · see citing works
Caspase-3 Is Required for DNA Fragmentation and Morphological Changes Associated with Apoptosis
Jänicke, R. U., Sprengart, M. L., Wati, M. R., & Porter, A. G. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.16.9357 · Cited by 1,955 · see citing works
Current Protocols in Molecular Biology
Teplitz, R. L. (1989) · JAMA · doi:10.1001/jama.1989.03420090114049 · Cited by 1,848 · see citing works
Galaxy: A Web‐Based Genome Analysis Tool for Experimentalists
Blankenberg, D. J., Kuster, G. V., Coraor, N., Ananda, G., Lazarus, R. M., Mangan, M. E., Nekrutenko, A., & Taylor, J. (2010) · Current Protocols in Molecular Biology · doi:10.1002/0471142727.mb1910s89 · Cited by 1,430 · see citing works
Unravelling mechanisms of p53-mediated tumour suppression
Bieging-Rolett, K. T., Mello, S. S., & Attardi, L. D. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3711 · Cited by 1,389 · see citing works
MDM2, MDMX and p53 in oncogenesis and cancer therapy
Wade, M., Li, Y.-C., & Wahl, G. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3430 · Cited by 1,279 · cited 1× · see citing works
“The most wellestablished mechanisms for this consist in the silencing of a negative regulator of Mdm2, p14ARF (the second product of the gene CDKN2A), or in the enhanced expression of the heterodimerization partner of Mdm2, MdmX/Mdm4 [2].”
BackgroundSelf-citationPost-translational modification of p53 in tumorigenesis
Bode, A. M., & Dong, Z. (2004) · Nature Reviews Cancer · doi:10.1038/nrc1455 · Cited by 1,270 · see citing works
iRegulon: From a Gene List to a Gene Regulatory Network Using Large Motif and Track Collections
Janky, R., Verfaillie, A., Imrichová, H., Van de Sande, B., Standaert, L., Christiaens, V., Hulselmans, G., Herten, K., Naval Sanchez, M., Potier, D., et al. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003731 · Cited by 900 · cited 3× · see citing works
“When comparing the induced genes with a database of promoters that had been found to associate with p53 in response to Nutlin ([40] Gene Omnibus database ID GSE47043), it turned out that the set of Nutlin-plusWip1i-inducible genes was highly enriched for promoter occupation by p53.”
BackgroundMethodInfluentialDrugging the p53 pathway: understanding the route to clinical efficacy
Khoo, K. H., Verma, C. S., & Lane, D. P. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4236 · Cited by 723 · see citing works
Chang, Y. S., Graves, B. J., Guerlavais, V., Tovar, C., Packman, K. E., To, K.-H., Olson, K. A., Kesavan, K. P., Gangurde, P., Mukherjee, A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1303002110 · Cited by 666 · see citing works
The BCL-2 protein family, BH3-mimetics and cancer therapy
Delbridge, A. R. D., & Strasser, A. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2015.50 · Cited by 538 · see citing works
Fiscella, M., Zhang, H., Fan, S., Sakaguchi, K., Shen, S., Mercer, W. E., Woude, G. F. V., O'Connor, P. M., & Appella, E. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.12.6048 · Cited by 527 · see citing works
p53-Responsive MicroRNAs 192 and 215 Are Capable of Inducing Cell Cycle Arrest
Braun, C. J., Zhang, X., Savelyeva, I., Wolff, S., Moll, U. M., Schepeler, T., Orntoft, T. F., Andersen, C. L., & Dobbelstein, M. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1569 · Cited by 467 · see citing works
Self-citationInside and out: the activities of senescence in cancer
Pérez-Mancera, P. A., Young, A. R. J., & Narita, M. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3773 · Cited by 462 · see citing works
Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity
Bulavin, D. V., Demidov, O. N., Saito, S., Kauraniemi, P., Dudgeon, C., Amundson, S. A., Ambrosino, C., Sauter, G., Nebreda, Á. R., Anderson, C. W., et al. (2002) · Nature Genetics · doi:10.1038/ng894 · Cited by 437 · see citing works
Takekawa, M., Adachi, M., Nakahata, A., Nakayama, I., Itoh, F., Tsukuda, H., Taya, Y., & Imai, K. (2000) · The EMBO Journal · doi:10.1093/emboj/19.23.6517 · Cited by 419 · see citing works
PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints
Lu, X., Nannenga, B., & Donehower, L. A. (2005) · Genes & Development · doi:10.1101/gad.1291305 · Cited by 389 · see citing works
Wip1 Phosphatase Modulates ATM-Dependent Signaling Pathways
Shreeram, S., Demidov, O. N., Hee, W. K., Yamaguchi, H., Onishi, N., Kek, C., Timofeev, O. N., Dudgeon, C., Fornace, A. J., Anderson, C. W., et al. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.07.010 · Cited by 350 · see citing works
The Wip1 Phosphatase Acts as a Gatekeeper in the p53-Mdm2 Autoregulatory Loop
Lu, X., Ma, O., Nguyen, T., Jones, S. N., Oren, M., & Donehower, L. A. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.08.033 · Cited by 282 · see citing works
Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer
Ruark, E., Snape, K. M. G., Humburg, P., Loveday, C., Bajrami, I., Brough, R., Rodrigues, D. N., Renwick, A., Seal, S., Ramsay, E., et al. (2012) · Nature · doi:10.1038/nature11725 · Cited by 247 · see citing works
Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23
Li, J., Yang, Y., Yue, P., Austin, R. J., van Eyndhoven, W., Nguyen, K. C. Q., Gabriele, T., McCurrach, M. E., Marks, J. R., Hoey, T. C., et al. (2002) · Nature Genetics · doi:10.1038/ng888 · Cited by 246 · see citing works
p21/CDKN1A Mediates Negative Regulation of Transcription by p53
Löhr, K., Möritz, C., Contente, A., & Dobbelstein, M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212517200 · Cited by 227 · see citing works
Self-citationAllosteric Wip1 phosphatase inhibition through flap-subdomain interaction
Gilmartin, A. G., Faitg, T. H., Richter, M. C., Groy, A., Seefeld, M. A., Darcy, M. G., Peng, X., Federowicz, K., Yang, J., Zhang, S., et al. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1427 · Cited by 207 · see citing works
Direct p53 Transcriptional Repression: In Vivo Analysis of CCAAT-Containing G2/M Promoters
Imbriano, C., Gurtner, A., Cocchiarella, F., Agostino, S. D., Basile, V., Gostissa, M., Dobbelstein, M., Sal, G. D., Piaggio, G., & Mantovani, R. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.9.3737-3751.2005 · Cited by 205 · see citing works
Self-citationActivation of p53 by MDM2 Antagonists Can Protect Proliferating Cells from Mitotic Inhibitors
Carvajal, D. M., Tovar, C., Yang, H. S., Vu, B. T., Heimbrook, D. C., & Vassilev, L. T. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3576 · Cited by 202 · see citing works
Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase
Fujimoto, H., Onishi, N., Kato, N., Takekawa, M., Xu, X. Z., Kosugi, A., Kondo, T., Imamura, M., Oishi, I., Yoda, A., et al. (2005) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401801 · Cited by 186 · see citing works
Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas
Zhang, L., Chen, L. H., Wan, H., Yang, R. R., Wang, Z., Feng, J., Yang, S., Jones, S., Wang, S., Zhou, W., et al. (2014) · Nature Genetics · doi:10.1038/ng.2995 · Cited by 185 · see citing works
Choi, M., Shi, J., Jung, S. H., Chen, X. X., & Cho, K. (2012) · Science Signaling · doi:10.1126/scisignal.2003363 · Cited by 170 · see citing works
Gain-of-function mutations of PPM1D/Wip1 impair the p53-dependent G1 checkpoint
Kleiblova, P., Shaltiel, I. A., Benada, J., Ševčík, J., Pecháčková, S., Pohlreich, P., Voest, E. E., Dundr, P., Bartek, J., Kleibl, Z., et al. (2013) · Journal of Cell Biology · doi:10.1083/jcb.201210031 · Cited by 170 · see citing works
Exploiting cancer cell cycling for selective protection of normal cells.
Blagosklonny, M. V., & Pardee, A. B. (2001) · PubMed · Cited by 157 · see citing works
Wip1 Directly Dephosphorylates γ-H2AX and Attenuates the DNA Damage Response
Cha, H., Lowe, J. M., Li, H., Lee, J., Belova, G. I., Bulavin, D. V., & Fornace, A. J. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-4244 · Cited by 151 · see citing works
Macůrek, L., Lindqvist, A., Voets, O., Kool, J., Vos, H. R., & Medema, R. H. (2010) · Oncogene · doi:10.1038/onc.2009.501 · Cited by 146 · see citing works
Apontes, P., Leontieva, O. V., Demidenko, Z. N., Li, F., & Blagosklonny, M. V. (2011) · Oncotarget · doi:10.18632/oncotarget.248 · Cited by 138 · see citing works
Genomic landscape of liposarcoma
Kanojia, D., Nagata, Y., Garg, M., Lee, D. H., Sato, A., Yoshida, K., Sato, Y., Sanada, M., Mayakonda, A., Bartenhagen, C., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.6464 · Cited by 132 · see citing works
Blagosklonny, M. V., Robey, R. W., Bates, S. E., & Fojo, T. (2000) · Journal of Clinical Investigation · doi:10.1172/jci8625 · Cited by 112 · see citing works
Wienken, M., Dickmanns, A., Nemajerová, A., Kramer, D., Najafova, Z., Weiss, M., Karpiuk, O., Kassem, M. S., Zhang, Y., Lozano, G., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.12.008 · Cited by 109 · see citing works
Self-citationQuaas, M., Müller, G. A., & Engeland, K. (2012) · Cell Cycle · doi:10.4161/cc.22917 · Cited by 107 · see citing works
The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase
Oliva-Trastoy, M., Berthonaud, V., Chevalier, A., Ducrot, C., Marsolier‐Kergoat, M., Mann, C., & Leteurtre, F. (2006) · Oncogene · doi:10.1038/sj.onc.1209927 · Cited by 107 · see citing works
Bill, K. L. J., Garnett, J., Meaux, I., Ma, X., Creighton, C. J., Bolshakov, S. V., Barrière, C., Debüssche, L., Lazar, A. J., Prudner, B. C., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1522 · 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
WIP1, a wound-inducible gene from maize with homology to Bowman-Birk proteinase inhibitors
Rohrmeier, T., & Lehle, L. (1993) · Plant Molecular Biology · doi:10.1007/bf00027365 · Cited by 87 · see citing works
Nongenotoxic p53 Activation Protects Cells against S-Phase–Specific Chemotherapy
Kranz, D., & Dobbelstein, M. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-1527 · Cited by 85 · see citing works
Self-citationCyclotherapy: Protection of Normal Cells and Unshielding of Cancer Cells
Blagosklonny, M. V., & Darżynkiewicz, Z. (2002) · Cell Cycle · doi:10.4161/cc.1.6.259 · Cited by 79 · see citing works
Lindqvist, A., de Bruijn, M., Macurek, L., Brás, A., Mensinga, A., Bruinsma, W., Voets, O., Kranenburg, O., & Medema, R. H. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.246 · Cited by 75 · see citing works
Pecháčková, S., Burdová, K., Benada, J., Kleiblová, P., Jeníková, G., & Macůrek, L. (2016) · Oncotarget · doi:10.18632/oncotarget.7363 · Cited by 75 · see citing works
Lambros, M. B. K., Natrajan, R., Geyer, F. C., López‐García, M. Á., Dedes, K. J., Savage, K., Lacroix‐Triki, M., Jones, R. L., Lord, C. J., Linardopoulos, S., et al. (2010) · Modern Pathology · doi:10.1038/modpathol.2010.121 · Cited by 72 · see citing works
Malonia, S. K., Dutta, P., Santra, M. K., & Green, M. R. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1510929112 · Cited by 66 · see citing works
Moon, S.-H., Nguyen, T., Darlington, Y. F., Lu, X., & Donehower, L. A. (2010) · Cell Cycle · doi:10.4161/cc.9.11.11810 · Cited by 66 · see citing works
Patnaik, A., Tolcher, A. W., Beeram, M., Nemunaitis, J. J., Weiss, G. J., Bhalla, K. N., Agrawal, M., NICHOLS, G. L., Middleton, S. A., Beryozkina, A., et al. (2015) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-015-2830-8 · Cited by 58 · see citing works
Esfandiari, A., Hawthorne, T. A., Nakjang, S., & Lunec, J. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0651 · Cited by 46 · see citing works
Shen, H., & Maki, C. G. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.124990 · Cited by 43 · see citing works
BRCA1 and Tip60 determine the cellular response to ultraviolet irradiation through distinct pathways
Kranz, D., Dohmesen, C., & Dobbelstein, M. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200712014 · Cited by 38 · see citing works
Self-citationBimodal regulation of p21waf1protein as function of DNA damage levels
Buscemi, G., Ricci, C., Zannini, L., Fontanella, E., Plevani, P., & Delia, D. (2014) · Cell Cycle · doi:10.4161/15384101.2014.946852 · Cited by 25 · see citing works
HDM2 promotes WIP1-mediated medulloblastoma growth
Buss, M. C., Read, T., Schniederjan, M., Gandhi, K., & Castellino, R. C. (2012) · Neuro-Oncology · doi:10.1093/neuonc/nos001 · Cited by 23 · see citing works
Li, Y., Saini, P., Sriraman, A., & Dobbelstein, M. (2015) · Oncotarget · doi:10.18632/oncotarget.5891 · Cited by 17 · see citing works
Self-citationWt p53 impairs response to chemotherapy: make lemonade to spare normal cells
Blagosklonny, M. V. (2012) · Oncotarget · doi:10.18632/oncotarget.548 · Cited by 14 · see citing works
Dobbelstein, M. (2012) · Cell Cycle · doi:10.4161/cc.23169 · Cited by 5 · see citing works
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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
Liu, Y., Wang, X., Wang, G., Yang, Y., Yuan, Y., & Ouyang, L. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.05.018 · Cited by 133 · see citing works
Genome-scale CRISPR-Cas9 screen identifies druggable dependencies in TP53 wild-type Ewing sarcoma
Stolte, B., Iniguez, A. B., Dharia, N. V., Robichaud, A. L., Conway, A. S., Morgan, A. M., Alexe, G., Schauer, N. J., Liu, X., Bird, G. H., et al. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20171066 · 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
Wu, C., Esfandiari, A., Ho, Y.-H., Wang, N., Mahdi, A. K., Aptullahoğlu, E., Lovat, P. E., & Lunec, J. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.433 · Cited by 62 · see citing works
The role of PPM1D in cancer and advances in studies of its inhibitors
Deng, W., Li, J., Dorrah, K., Jimenez-Tapia, D., Arriaga, B., Hao, Q., Cao, W., Gao, Z., Vadgama, J. V., & Wu, Y. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.109956 · Cited by 57 · see citing works
WIP1 phosphatase as pharmacological target in cancer therapy
Pecháčková, S., Burdová, K., & Macůrek, L. (2017) · Journal of Molecular Medicine · doi:10.1007/s00109-017-1536-2 · Cited by 56 · see citing works
Choi, M., Shi, J., Zhu, Y., Yang, R., & Cho, K. (2017) · Nature Communications · doi:10.1038/s41467-017-02160-5 · Cited by 50 · see citing works
Kocik, J., Machula, M., Wisniewska, A., Surmiak, E., Holak, T. A., & Skalniak, L. (2019) · Cancers · doi:10.3390/cancers11071014 · Cited by 46 · see citing works
CDK4 inhibition diminishes p53 activation by MDM2 antagonists
Sriraman, A., Dickmanns, A., Najafova, Z., Johnsen, S. A., & Dobbelstein, M. (2018) · Cell Death & Disease · doi:10.1038/s41419-018-0968-0 · Cited by 40 · see citing works
Self-citationWip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis
Chen, Z., Wang, L., Yao, D., Yang, T., Cao, W., Dou, J., Pang, J. C., Guan, S., Zhang, H., Yu, Y., et al. (2016) · Scientific Reports · doi:10.1038/srep38011 · Cited by 39 · see citing works
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Zhou, X. Y., Cao, B., & Lu, H. (2017) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjx001 · Cited by 36 · see citing works
Marengo, B., Monti, P., Miele, M., Menichini, P., Ottaggio, L., Foggetti, G., Pulliero, A., Izzotti, A., Speciale, A., Garbarino, O., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-32195-7 · Cited by 35 · see citing works
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Burdová, K., Storchova, R., Palek, M., & Macůrek, L. (2019) · Cells · doi:10.3390/cells8101258 · Cited by 31 · see citing works
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Sherekar, S., & Viswanathan, G. A. (2021) · Computational and Systems Oncology · doi:10.1002/cso2.1017 · Cited by 29 · see citing works
Andrysík, Z., Sullivan, K. D., Kieft, J. S., & Espinosa, J. M. (2022) · Nature Communications · doi:10.1038/s41467-022-35089-5 · Cited by 31 · see citing works
Magri, J., Gasparetto, A., Conti, L., Calautti, E., Cossu, C., Ruiu, R., Barutello, G., & Cavallo, F. (2021) · Cells · doi:10.3390/cells10010108 · Cited by 29 · see citing works
Raab, M., Kostova, I., Peña‐Llopis, S., Fietz, D., Kressin, M., Aberoumandi, S. M., Ullrich, E., Becker, S., Sanhaji, M., & Strebhardt, K. (2023) · 癌症：英文版 · doi:10.1002/cac2.12511 · Cited by 27 · see citing works
Wang, P., Zhao, Y., Liu, K., Liu, X., Liang, J., Zhou, H., Wang, Z., Zhou, Z., & Xu, N. (2019) · Journal of Cellular Biochemistry · doi:10.1002/jcb.28840 · Cited by 24 · see citing works
Protein phosphatase, Mg2+/Mn2+‐dependent 1D (PPM1D) mutations in haematological cancer
Husby, S., Justesen, E. H., & Grønbæk, K. (2020) · British Journal of Haematology · doi:10.1111/bjh.17120 · Cited by 21 · see citing works
Analysis framework and experimental design for evaluating synergy-driving gene expression
Schrode, N., Seah, C., Deans, P. J. M., Hoffman, G. E., & Brennand, K. (2021) · Nature Protocols · doi:10.1038/s41596-020-00436-7 · Cited by 19 · see citing works
Nahta, R., & Castellino, R. C. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114362 · Cited by 19 · see citing works
Tesson, M., Vasan, R., Hock, A., Nixon, C., Rae, C. J., Gaze, M. N., & Mairs, R. J. (2018) · Oncotarget · doi:10.18632/oncotarget.25607 · Cited by 18 · see citing works
Harnessing p53 for targeted cancer therapy: new advances and future directions
Andrysík, Z., & Espinosa, J. M. (2025) · Transcription · doi:10.1080/21541264.2025.2452711 · Cited by 18 · see citing works
Wip1: A candidate phosphatase for cancer diagnosis and treatment
Bakhshaiesh, T. O., Majidzadeh‐A, K., & Esmaeili, R. (2017) · DNA repair · doi:10.1016/j.dnarep.2017.03.004 · Cited by 15 · see citing works
Inhibition of invasive pancreatic cancer: restoring cell apoptosis by activating mitochondrial p53.
Cheng, J., Okolotowicz, K. J., Ryan, D., Mose, E. S., Lowy, A. M., & Cashman, J. R. (2019) · Europe PMC (PubMed Central) · Cited by 13 · see citing works
Shi, L., Tian, Q., Feng, C., Zhang, P., & Zhao, Y. X. (2020) · International Reviews of Immunology · doi:10.1080/08830185.2020.1795153 · Cited by 11 · see citing works
Wu, C., Mahdi, A., Huang, C., Chen, C., Pan, Y., Chang, J. W., Chen, J., Yeh, C., & Lunec, J. (2021) · Cancers · doi:10.3390/cancers13153876 · Cited by 11 · see citing works
In vitro and in vivo study of GSK2830371 and RG7388 combination in liver adenocarcinoma.
Wu, C., Chen, C., Pan, Y., Jung, S., Chang, J. W., Chen, J., Yeh, C., & Lunec, J. (2022) · PubMed Central · Cited by 10 · see citing works
PP2C phosphatases—terminators of suicidal thoughts
Lagorgette, L., Bogdanova, D. A., Belotserkovskaya, E., Garrido, C., & Demidov, O. N. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-07269-2 · Cited by 9 · see citing works
Zanjirband, M., Rahgozar, S., & Aberuyi, N. (2023) · Cancer Drug Resistance · doi:10.20517/cdr.2022.113 · Cited by 9 · see citing works
Inoue, Y., Yamashita, N., Kitao, H., Tanaka, K., Saeki, H., Oki, E., Oda, Y., Tokunaga, E., & Maehara, Y. (2017) · Clinical Breast Cancer · doi:10.1016/j.clbc.2017.11.008 · Cited by 8 · see citing works
Chamberlain, V., Drew, Y., & Lunec, J. (2021) · Cancers · doi:10.3390/cancers14010014 · Cited by 9 · see citing works
Wu, L., Yang, Y., Wang, Z., Wu, X., Su, F., Li, M., Jing, X., & Han, C. (2020) · Molecules · doi:10.3390/molecules25051162 · Cited by 7 · see citing works
Fortifying p53 – beyond Mdm2 inhibitors
Sriraman, A., Li, Y., & Dobbelstein, M. (2016) · Aging · doi:10.18632/aging.101073 · Cited by 6 · see citing works
Self-citationPAWI-2: A novel inhibitor for eradication of cancer
Cheng, J., & Cashman, J. R. (2020) · Medicinal Chemistry Research · doi:10.1007/s00044-020-02575-8 · Cited by 5 · see citing works
The evolution of Nutlins as p53-MDM2 inhibitors
Bazanov, D. R., & Lozinskaya, N. A. (2025) · Medicinal Chemistry Research · doi:10.1007/s00044-025-03492-4 · Cited by 3 · see citing works
Xing, Z., Xu, H., Lin, P.-X., Hong, Y.-L., Shao, S., Yang, T., Li, Y., & Wei, Y.-B. (2026) · British Journal of Cancer · doi:10.1038/s41416-026-03364-7 · Cited by 1 · see citing works
Self-citationResearch Progress on Small Molecule Inhibitors of MDM2-p53 Protein-protein Interaction
Hu, M. Y., Xu, C., Xu, M., He, S., & Liu, D. (2025) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/0118715206358340250121060830 · Cited by 1 · see citing works
Tarazona, M. Y. C., & Miscione, G. P. (2026) · Frontiers in Drug Discovery · doi:10.3389/fddsv.2025.1731262 · Cited by 1 · see citing works
Epigenetic regulation of osteoblast differentiation
Najafova, Z. (2017) · doi:10.53846/goediss-6333 · Cited by 1 · see citing works
Self-citationInhibition of the kinase Wee1 - Cytotoxic mechanisms and autoprotection by the tumor suppressor p53
Li, Y. (2017) · doi:10.53846/goediss-6554
Self-citationTargeting MDM2, the antagonist of the tumor suppressor p53
Sriraman, A. (2018) · doi:10.53846/goediss-7056
Self-citationFluoride-induced vascular endothelial injury and the protective mechanism of blueberry anthocyanins
Zhang, C., Wang, Y., Huang, F., Zhang, Y., Huang, M., Liu, Y., Angwa, L. M., Gao, Y., Sun, D., & Jiang, Y. (2025) · Food and Chemical Toxicology · doi:10.1016/j.fct.2025.115665
- Authors
- Sriraman, A., Radovanovic, M., Wienken, M., Najafova, Z., Li, Y., & Dobbelstein, M.
- Affiliations
- Universitätsmedizin Göttingen (DE)
- Corresponding author
- Li, Yizhu
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2016-05-11
- Volume
- 7
- Issue
- 22
- Pages
- 31623-31638
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC5077964
- OpenAlex
- W2382465108
- Cited by
- 44
- References
- 67
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 6 · 2020: 6 · 2019: 5 · 2018: 5 · 2017: 8 · 2016: 3
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- GRO (submittedVersion, cc-by)
- Funders
- Studienstiftung des Deutschen Volkes
- José Carreras Leukämie-Stiftung
- Deutsche Krebshilfe
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- Nutlin-3a, MDM2 inhibitors, p53 activation, combination therapy, p53 phosphorylation, p53 acetylation, cellular senescence, G2/M cell cycle arrest, tumor suppression, p53-deficient cells
- MeSH terms
- Protein Phosphatase 2C, Acetylation, Aminopyridines, Antineoplastic Combined Chemotherapy Protocols, Dipeptides, Dose-Response Relationship, Drug, Drug Synergism, Enzyme Inhibitors, Humans, Imidazoles, Neoplasms, Phosphorylation, Piperazines, Time Factors, Transfection, Signal Transduction, Up-Regulation, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Cellular Senescence, RNA Interference, HCT116 Cells, Cell Proliferation, Proto-Oncogene Proteins c-mdm2, Transcriptome, G2 Phase Cell Cycle Checkpoints, MCF-7 Cells
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