Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2.
Open accessAbstract
The p53 tumor suppressor protein has a major role in protecting the integrity of the genome. In unstressed cells, p53 is maintained at low levels by the ubiquitin-proteasome pathway. A balance between ubiquitin ligase activity (Hdm2, COP1, and Pirh2) and the ubiquitin protease activity of the Herpes virus-associated ubiquitin-specific protease (HAUSP) determines the half-life of p53. HAUSP also modulates p53 stability indirectly by deubiquitination and stabilization of Hdm2. The Hdmx protein affects p53 stability as well through its interaction with and regulation of Hdm2. Vice versa, Hdmx is a target for Hdm2-mediated ubiquitination and degradation. Here, we show that HAUSP also interacts with Hdmx, resulting in its direct deubiquitination and stabilization. HAUSP activity is required to maintain normal Hdmx protein levels. Therefore, the balance between HAUSP and Hdm2 activity determines Hdmx protein stability. Importantly, impaired deubiquitination of Hdmx/Hdm2 by HAUSP contributes to the DNA damage-induced degradation of Hdmx and transient instability of Hdm2.
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USP7 deubiquitinates and stabilizes Mdm4 (also known as Mdmx).
“Furthermore, USP7 deubiquitinates and stabilizes the Mdm2 interacting partner – and substrate (Kawai et al., 2003; Pan and Chen, 2003) – Mdm4 (also known as Mdmx) (Meulmeester et al., 2005).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Meulmeester et al., 2005
Hausp also deubiquitinates Mdm4, another inhibitor of p53 activity.
“More recent data suggest that Hausp also deubiquitinates Mdm4, another inhibitor of p53 activity (Meulmeester, et al., 2005).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Meulmeester, et al., 2005
HAUSP is a deubiquitylase that binds to and stabilizes Mdm2 and Mdmx preferentially under normal growth conditions.
“For example, HAUSP is a deubiquitylase (DUB) that binds to and stabilizes Mdm2 and Mdmx preferentially under normal growth conditions [45,46].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [46]
Cites
Mdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506 · see citing works
Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312 · see citing works
The β-Catenin/TCF-4 Complex Imposes a Crypt Progenitor Phenotype on Colorectal Cancer Cells
van de Wetering, M., Sancho, E., Verweij, C., de Lau, W., Oving, I., Hurlstone, A., van der Horn, K., Batlle, E., Coudreuse, D., Haramis, A.-P., et al. (2002) · Cell · doi:10.1016/s0092-8674(02)01014-0 · Cited by 2,030 · see citing works
Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53
de Oca Luna, R. M., Wagner, D. S., & Lozano, G. (1995) · Nature · doi:10.1038/378203a0 · Cited by 1,420 · see citing works
Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53
Jones, S. N., Roe, A. E., Donehower, L. A., & Bradley, A. (1995) · Nature · doi:10.1038/378206a0 · Cited by 1,280 · cited 1× · see citing works
“Because mdm2-knockout mice are also embryonic lethal in a p53-dependent manner (Montes de Oca Luna et al., 1995; Jones et al., 1995), it suggests that in early embryonic life, Mdmx and Mdm2 cannot substitute for one another.”
BackgroundDeubiquitination of p53 by HAUSP is an important pathway for p53 stabilization
Li, M., Chen, D., Shiloh, A., Luo, J., Nikolaev, A. Y., Qin, J., & Gu, W. J. (2002) · Nature · doi:10.1038/nature737 · Cited by 1,027 · see citing works
Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB
Brummelkamp, T. R., Nijman, S. M. B., Dirac, A. M. G., & Bernards, R. (2003) · Nature · doi:10.1038/nature01811 · Cited by 947 · see citing works
A dynamic role of HAUSP in the p53-Mdm2 pathway
Li, M., Brooks, C. L., Kon, N., & Gu, W. (2004) · Molecular Cell · doi:10.1016/s1097-2765(04)00157-1 · Cited by 679 · see citing works
MDMX: a novel p53‐binding protein with some functional properties of MDM2.
Shvarts, A., Steegenga, W. T., Riteco, N., van Laar, T., Dekker, P., Bazuine, M., van Ham, R. C., van der Houven van Oordt, W., Hateboer, G., van der Eb, A. J., et al. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00919.x · Cited by 648 · see citing works
Self-citationPrives, C. (1998) · Cell · doi:10.1016/s0092-8674(00)81774-2 · Cited by 623 · see citing works
Parant, J., Chavez-Reyes, A., Little, N. A., Yan, W., Reinke, V., Jochemsen, A. G., & Lozano, G. (2001) · Nature Genetics · doi:10.1038/ng714 · Cited by 517 · see citing works
Self-citationvan de Wetering, M., Oving, I. M., Muncan, V., Fong, M. T. P., Brantjes, H., van Leenen, D., Holstege, F. C. P., Brummelkamp, T. R., Agami, R., & Clevers, H. C. (2003) · EMBO Reports · doi:10.1038/sj.embor.embor865 · Cited by 512 · see citing works
Everett, R. D., Meredith, M., Orr, A., Cross, A., Kathoria, M., & Parkinson, J. (1997) · The EMBO Journal · doi:10.1093/emboj/16.7.1519 · Cited by 491 · see citing works
Accelerated MDM2 auto‐degradation induced by DNA‐damage kinases is required for p53 activation
Stommel, J. M., & Wahl, G. M. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600145 · Cited by 386 · see citing works
Disruption of HAUSP gene stabilizes p53.
Cummins, J. M., Rago, C., Kohli, M., Kinzler, K. W., Lengauer, C., & Vogelstein, B. (2004) · Nature · doi:10.1038/nature02501 · Cited by 379 · see citing works
HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53
Linares, L. K., Hengstermann, A., Ciechanover, A., Müller, S., & Scheffner, M. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2030930100 · Cited by 361 · see citing works
Migliorini, D., Denchi, E. L., Danovi, D., Jochemsen, A., Capillo, M., Gobbi, A., Helin, K., Pelicci, P. G., & Marine, J.-C. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.15.5527-5538.2002 · Cited by 313 · see citing works
Self-citationDanovi, D., Meulmeester, E., Pasini, D., Migliorini, D., Capra, M., Frenk, R., de Graaf, P., Francoz, S., Gasparini, P., Gobbi, A., et al. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.13.5835-5843.2004 · Cited by 310 · see citing works
Self-citationThe p53 and Mdm2 families in cancer
Michael, D. (2002) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(01)00264-7 · Cited by 288 · see citing works
A monoclonal antibody recognizing nuclear matrix-associated nuclear bodies
Stuurman, N., de Graaf, A., Floore, A., Josso, A., Humbel, B. M., de Jong, L., & DRIEL, R. V. (1992) · Journal of Cell Science · doi:10.1242/jcs.101.4.773 · Cited by 256 · see citing works
MDM2 promotes ubiquitination and degradation of MDMX
Pan, Y., & Chen, J. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.15.5113-5121.2003 · Cited by 246 · cited 5× · see citing works
“DNA Damage-Induced Degradation of Hdmx Is Not Rescued by HAUSP Previous studies have shown that the Hdmx protein is degraded upon treatment of cells with DNA damaging agents in an Hdm2- and proteasome-dependent manner (Pan and Chen, 2003; Kawai et al., 2003a).”
BackgroundResultInfluentialMdmx stabilizes p53 and Mdm2 via two distinct mechanisms
Stad, R., Little, N. A., Xirodimas, D. P., Frenk, R., van der Eb, A. J., Lane, D. P., Saville, M. K., & Jochemsen, A. G. (2001) · The EMBO Reports · doi:10.1093/embo-reports/kve227 · Cited by 234 · see citing works
Self-citationMdmX Protects p53 from Mdm2-Mediated Degradation
Jackson, M. W., & Berberich, S. J. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.3.1001-1007.2000 · Cited by 211 · cited 1× · see citing works
“Although Hdmx lacks detectable E3 ubiquitin ligase activity in cells and is unable to degrade p53, Hdmx can inhibit transcription activation by p53 (Jackson and Berberich, 2000; Stad et al., 2001).”
Backgroundmdmx is a negative regulator of p53 activity in vivo.
Finch, R. A., Donoviel, D. B., Potter, D., Shi, M., Fan, A., Freed, D. D., Wang, C.-Y., Zambrowicz, B., Ramírez‐Solis, R., Sands, A., et al. (2002) · PubMed · Cited by 192 · see citing works
Ovaa, H., Kessler, B. M., Rolén, U., Galardy, P. J., Ploegh, H. L., & Masucci, M. G. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308411100 · Cited by 190 · see citing works
Self-citationComparative 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
Self-citationPhosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage
Pereg, Y., Shkedy, D., de Graaf, P., Meulmeester, E., Edelson-Averbukh, M., Salek, M., Biton, S., Teunisse, A. F. A. S., Lehmann, W. D., Jochemsen, A. G., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408595102 · Cited by 181 · see citing works
Self-citationDNA damage-induced MDMX degradation is mediated by MDM2
Kawai, H., Wiederschain, D., Kitao, H., Stuart, J., Tsai, K. K. C., & Yuan, Z.-M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m308295200 · Cited by 163 · cited 1× · see citing works
“Lastly, treatment of cells with DNA damaging agents results in an Hdm2-dependent degradation of Hdmx (Pan and Chen, 2003; Kawai et al., 2003a). Remarkably, we find that ectopically expressed HAUSP is unable to rescue DNA damagemediated degradation of Hdmx. It could be hypothesized that not the decrease in HAUSP activi…”
BackgroundAberrant expression of HDMX proteins in tumor cells correlates with wild-type p53.
Ramos, Y. F., Stad, R. K., Attema, J., Peltenburg, L. T. C., van der Eb, A. J., & Jochemsen, A. G. (2001) · PubMed · Cited by 149 · see citing works
Self-citationHdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2
de Graaf, P., Little, N. A., Ramos, Y. F. M., Meulmeester, E., Letteboer, S. J. F., & Jochemsen, A. G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213034200 · Cited by 143 · see citing works
Self-citationCanning, M., Boutell, C., Parkinson, J., & Everett, R. D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402885200 · Cited by 142 · see citing works
Self-citationThe Herpes Simplex Virus Type 1 (HSV-1) Regulatory Protein ICP0 Interacts with and Ubiquitinates p53
Boutell, C., & Everett, R. D. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300776200 · Cited by 140 · see citing works
Self-citationCritical Contribution of the MDM2 Acidic Domain to p53 Ubiquitination
Kawai, H., Wiederschain, D., & Yuan, Z.-M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.14.4939-4947.2003 · Cited by 122 · see citing works
Critical Role for a Central Part of Mdm2 in the Ubiquitylation of p53
Meulmeester, E., Frenk, R., Stad, R. K., de Graaf, P., Marine, J., Vousden, K. H., & Jochemsen, A. G. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.14.4929-4938.2003 · Cited by 113 · see citing works
Self-citationHigh expression of the HMG box factor Sox-13 in arterial walls during embryonic development
Roose, J. P., Korver, W., Oving, E., Wilson, A., Wagenaar, G. T. M., Markman, M. W. M., Lamers, W. H., & Clevers, H. C. (1998) · Nucleic Acids Research · doi:10.1093/nar/26.2.469 · Cited by 45 · see citing works
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2 of the 37 references couldn’t be matched to a known paper.
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Sorted by citations
Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
Toledo, F., & Wahl, G. M. (2006) · Nature reviews. Cancer · doi:10.1038/nrc2012 · Cited by 1,286 · see citing works
p53 ubiquitination: Mdm2 and beyond
Brooks, C. L., & Gu, W. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.020 · Cited by 924 · see citing works
USP10 Regulates p53 Localization and Stability by Deubiquitinating p53
Yuan, J., Luo, K., Zhang, L., Cheville, J. C., & Lou, Z. (2010) · Cell · doi:10.1016/j.cell.2009.12.032 · Cited by 637 · see citing works
“Furthermore, ATM-dependent phosphorylation of Mdm2 and Mdmx could destabilize these proteins and compromise their activity (Khosravi et al., 1999; Maya et al., 2001; Meulmeester et al., 2005; Pereg et al., 2005; Stommel and Wahl, 2004).”
Tumour suppression by p53: a role for the DNA damage response?
Meek, D. W. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2716 · Cited by 604 · see citing works
Chauhan, D., Tian, Z., Nicholson, B., Kumar, K. G. S., Zhou, B., Carrasco, R., McDermott, J. L., Leach, C. A., Fulcinniti, M., Kodrasov, M. P., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.08.007 · Cited by 589 · see citing works
Coping with stress: multiple ways to activate p53
Horn, H. F., & Vousden, K. H. (2007) · Oncogene · doi:10.1038/sj.onc.1210263 · Cited by 522 · see citing works
p53 post-translational modification: deregulated in tumorigenesis
Dai, C., & Gu, W. J. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.09.002 · Cited by 523 · see citing works
FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP
van der Horst, A., de Vries-Smits, A. M. M., Brenkman, A. B., van Triest, M. H., van den Broek, N. J. F., Colland, F., Maurice, M. M., & Burgering, B. M. T. (2006) · Nature Cell Biology · doi:10.1038/ncb1469 · Cited by 479 · see citing works
Self-citationThe p53 orchestra: Mdm2 and Mdmx set the tone
Wade, M., Wang, Y. V., & Wahl, G. M. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.01.009 · Cited by 450 · see citing works
Regulating tumor suppressor genes: post-translational modifications
Chen, L., Liu, S., & Tao, Y. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0196-9 · Cited by 449 · see citing works
Activity-Based Chemical Proteomics Accelerates Inhibitor Development for Deubiquitylating Enzymes
Altun, M., Kramer, H., Willems, L. I., McDermott, J. L., Leach, C. A., Goldenberg, S. J., Kumar, S., Konietzny, R., Fischer, R., Kogan, E., et al. (2011) · Chemistry & Biology · doi:10.1016/j.chembiol.2011.08.018 · Cited by 401 · see citing works
p53 and breast cancer, an update
Lacroix, M., Toillon, R., & Leclercq, G. (2006) · Endocrine Related Cancer · doi:10.1677/erc.1.01172 · Cited by 380 · see citing works
Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells
Colland, F., Formstecher, É., Jacq, X., Reverdy, C., Planquette, C., Conrath, S., Trouplin, V., Bianchi, J., Aushev, V. N., Camonis, J., et al. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0097 · Cited by 322 · see citing works
The predator becomes the prey: regulating the ubiquitin system by ubiquitylation and degradation
Weissman, A. M., Shabek, N., & Ciechanover, A. J. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3173 · Cited by 318 · see citing works
van Loosdregt, J., Fleskens, V., Fu, J., Brenkman, A., Bekker, C., Pals, C., Meerding, J., Berkers, C., Barbi, J., Gröne, A., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.05.018 · Cited by 325 · see citing works
Self-citationMolecular recognition of p53 and MDM2 by USP7/HAUSP.
Sheng, Y., Saridakis, V., Sarkari, F., Duan, S., Wu, T., Arrowsmith, C. H., & Frappier, L. (2006) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1067 · Cited by 315 · see citing works
The multiple levels of regulation by p53 ubiquitination
Lee, J. T., & Gu, W. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.77 · Cited by 289 · see citing works
Regulation of the p53 response and its relationship to cancer
Meek, D. W. (2015) · Biochemical Journal · doi:10.1042/bj20150517 · Cited by 291 · see citing works
Monoubiquitylation promotes mitochondrial p53 translocation
Marchenko, N. D., Wolff, S., Erster, S., Becker, K., & Moll, U. M. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601560 · Cited by 286 · see citing works
UV-sensitive syndrome protein UVSSA recruits USP7 to regulate transcription-coupled repair
Schwertman, P., Lagarou, A., Dekkers, D. H. W., Raams, A., van der Hoek, A. C., Laffeber, C., Hoeijmakers, J. H. J., Demmers, J. A. A., Fousteri, M., Vermeulen, W., et al. (2012) · Nature Genetics · doi:10.1038/ng.2230 · Cited by 279 · see citing works
A Stapled p53 Helix Overcomes HDMX-Mediated Suppression of p53
Bernal, F., Wade, M. R., Godes, M., Davis, T. N., Whitehead, D. G., Kung, A. L., Wahl, G. M., & Walensky, L. D. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.10.024 · Cited by 284 · see citing works
The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2
Stevenson, L. F., Sparks, A., Allende‐Vega, N., Xirodimas, D. P., Lane, D. P., & Saville, M. K. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601567 · Cited by 280 · 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
Abuetabh, Y., Wu, H. H., Chai, C., Yousef, H. A., Persad, S., Sergi, C. M., & Leng, R. P. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00863-4 · Cited by 275 · see citing works
Bougdour, A., Durandau, E., Brenier‐Pinchart, M., Ortet, P., Barakat, M., Kieffer‐Jaquinod, S., Curt, A., Bertini, R., Bastien, O., Couté, Y., et al. (2013) · Cell Host & Microbe · doi:10.1016/j.chom.2013.03.002 · Cited by 258 · see citing works
Faesen, A. C., Dirac, A. M. G., Shanmugham, A., Ovaa, H., Anastassis Perrakis, A., & Sixma, T. K. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.06.034 · Cited by 251 · see citing works
Self-citationHu, M., Gu, L., Li, M., Jeffrey, P. D., Gu, W., & Shi, Y. (2006) · PLoS Biology · doi:10.1371/journal.pbio.0040027 · Cited by 251 · see citing works
Mechanism of p53 stabilization by ATM after DNA damage
Cheng, Q., & Chen, J. (2010) · Cell Cycle · doi:10.4161/cc.9.3.10556 · Cited by 248 · see citing works
The Multifaceted Roles of USP7: New Therapeutic Opportunities
Nicholson, B., & Kumar, S. (2011) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-011-9185-5 · Cited by 243 · see citing works
Critical role for Daxx in regulating Mdm2
Tang, J., Qu, L., Zhang, J., Wang, W., Michaelson, J. S., Degenhardt, Y., El‐Deiry, W. S., & Yang, X. (2006) · Nature Cell Biology · doi:10.1038/ncb1442 · Cited by 239 · see citing works
Suppression of Cancer Cell Growth by Promoting Cyclin D1 Degradation
Shan, J., Zhao, W., & Gu, W. J. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.10.018 · Cited by 229 · see citing works
Marine, J.-C. W., Dyer, M. A., & Jochemsen, A. G. (2007) · Journal of Cell Science · doi:10.1242/jcs.03362 · Cited by 228 · see citing works
Self-citationStabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis.
Wang, Q., Ma, S., Song, N., Li, X., Liu, L., Yang, S., Ding, X., Shan, L., Zhou, X., Su, D., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci85747 · Cited by 206 · see citing works
Toledo, F., Krummel, K. A., Lee, C. J., Liu, C.-W., Rodewald, L.-W., Tang, M., & Wahl, G. M. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.03.014 · Cited by 199 · see citing works
Dayal, S., Sparks, A., Jacob, J., Allende-Vega, N., Lane, D. P., & Saville, M. K. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805871200 · Cited by 200 · see citing works
Felle, M., Joppien, S., Németh, A., Diermeier, S. D., Thalhammer, V., Dobner, T., Kremmer, E., Kappler, R., & Längst, G. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr528 · Cited by 198 · see citing works
Positive regulation of p53 stability and activity by the deubiquitinating enzyme Otubain 1
Sun, X., Challagundla, K. B., & Dai, M. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.434 · Cited by 194 · 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
Brooks, C. L., & Gu, W. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.05.022 · Cited by 186 · see citing works
Protein partners of deubiquitinating enzymes
Ventii, K., & Wilkinson, K. D. (2008) · Biochemical Journal · doi:10.1042/bj20080798 · Cited by 185 · see citing works
Regulation of proteolysis by human deubiquitinating enzymes
Eletr, Z. M., & Wilkinson, K. D. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.06.027 · Cited by 183 · see citing works
Inactivation of HAUSP in vivo modulates p53 function.
Kon, N., Kobayashi, Y., Li, M., Brooks, C. L., Ludwig, T., & Gu, W. (2010) · Oncogene · doi:10.1038/onc.2009.427 · Cited by 176 · see citing works
The Regulation of Multiple p53 Stress Responses is Mediated through MDM2
Hu, W., Feng, Z., & Levine, A. J. (2012) · Genes & Cancer · doi:10.1177/1947601912454734 · Cited by 176 · see citing works
An essential function of the extreme C-terminus of MDM2 can be provided by MDMX
Uldrijan, S., Pannekoek, W., & Vousden, K. H. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601469 · Cited by 170 · see citing works
Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry?
Wade, M., & Wahl, G. M. (2009) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-08-0423 · Cited by 170 · see citing works
The role of ubiquitin modification in the regulation of p53
Hock, A. K., & Vousden, K. H. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.05.022 · Cited by 168 · see citing works
ATM-Mediated Phosphorylations Inhibit Mdmx/Mdm2 Stabilization by HAUSP in Favor of p53 Activation
Meulmeester, E., Pereg, Y., Shiloh, Y., & Jochemsen, A. G. (2005) · Cell Cycle · doi:10.4161/cc.4.9.1981 · Cited by 166 · see citing works
Self-citationLimiting the power of p53 through the ubiquitin proteasome pathwayPreprint
Pant, V., & Lozano, G. (2014) · Genes & Development · doi:10.1101/gad.247452.114 · Cited by 165 · see citing works
Hdmx modulates the outcome of p53 activation in human tumor cells
Wade, M., Wong, E. T., Tang, M., Stommel, J. M., & Wahl, G. M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605405200 · Cited by 163 · see citing works
Usp7 and Uhrf1 control ubiquitination and stability of the maintenance DNA methyltransferase Dnmt1
Qin, W., Leonhardt, H., & Spada, F. (2010) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22998 · Cited by 163 · see citing works
Novellasdemunt, L., Foglizzo, V., Gómez-Cuadrado, L., Antas, P., Kucharska, A., Encheva, V., Snijders, A. P., & Li, V. S. W. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.072 · Cited by 163 · see citing works
Qi, S., Cheng, G., Cheng, X., Xu, Z., Xu, B., Zhang, W., & Qin, J. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00233 · Cited by 162 · see citing works
Deubiquitinases as a Signaling Target of Oxidative Stress
Cotto-Rios, X. M., Békés, M., Chapman, J. R., Ueberheide, B. M., & Huang, T. T. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.11.011 · Cited by 161 · see citing works
ATM-Dependent Downregulation of USP7/HAUSP by PPM1G Activates p53 Response to DNA Damage
Khoronenkova, S. V., Dianova, I. I., Ternette, N., Kessler, B. M., Parsons, J. L., & Dianov, G. L. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.01.021 · Cited by 146 · see citing works
The p53–Mdm2–HAUSP complex is involved in p53 stabilization by HAUSP
Brooks, C. L., Li, M., Hu, M., Shi, Y., & Gu, W. (2007) · Oncogene · doi:10.1038/sj.onc.1210531 · Cited by 144 · see citing works
Targeting ubiquitin specific proteases for drug discovery
Daviet, L., & Colland, F. (2007) · Biochimie · doi:10.1016/j.biochi.2007.09.013 · Cited by 139 · see citing works
Deubiquitinases and the new therapeutic opportunities offered to cancer
Pfoh, R., Lacdao, I. K., & Saridakis, V. (2015) · Endocrine Related Cancer · doi:10.1530/erc-14-0516 · Cited by 140 · see citing works
Song, M. S., Song, S. J., Kim, S. Y., Oh, H. J., & Lim, D. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.115 · Cited by 134 · see citing works
Protein degradation and the stress response
Flick, K. M., & Kaiser, P. (2012) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2012.01.019 · Cited by 133 · see citing works
Nucleotide Biosynthetic Enzyme GMP Synthase Is a TRIM21-Controlled Relay of p53 Stabilization
Reddy, B. A., van der Knaap, J. A., Bot, A. G. M., Mohd-Sarip, A., Dekkers, D. H. W., Timmermans, M. A. M., Martens, J. W. M., Demmers, J., & Verrijzer, C. P. (2014) · Molecular Cell · doi:10.1016/j.molcel.2013.12.017 · Cited by 131 · see citing works
USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin
Ji, L., Lu, B., Zamponi, R., Charlat, O., Aversa, R. J., Yang, Z., Sigoillot, F. D., Zhu, X., Hu, T., Reece-Hoyes, J. S., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12143-3 · Cited by 129 · see citing works
Wu, H.-T., Kuo, Y.-C., Hung, J.-J., Huang, C.-H., Chen, W.-Y., Chou, T.-Y., Chen, Y., Chen, Y.-J., Chen, Y.-J., Cheng, W.-C., et al. (2016) · Nature Communications · doi:10.1038/ncomms13644 · Cited by 129 · see citing works
MDM2 and MDMX: Alone and together in regulation of p53.
Shadfan, M., Lopez-Pajares, V., & Yuan, Z.-M. (2012) · PubMed · Cited by 125 · see citing works
Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3
LeBron, C., Chen, L., Gilkes, D. M., & Chen, J. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601032 · Cited by 122 · see citing works
Cai, J., Shi, G., Dong, Z., Ke, A., Ma, H., Gao, Q., Shen, Z., Huang, X., Chen, H., Yu, D., et al. (2014) · Hepatology · doi:10.1002/hep.27682 · Cited by 123 · see citing works
Regulation of p53 stability and function by the deubiquitinating enzyme USP42
Hock, A. K., Vigneron, A. M., Carter, S., Ludwig, R. L., & Vousden, K. H. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.419 · Cited by 117 · see citing works
USP7 Is a Master Regulator of Genome Stability
Valles, G. J., Bezsonova, I., Woodgate, R., & Ashton, N. W. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00717 · Cited by 114 · see citing works
“UBL 4–5 has also been speculated to contain a secondary binding site outside of the TRAF-like domain for binding to p53 and Mdm2, although further validation of this site is still needed (Ma et al., 2010; Kim et al., 2019).”
BackgroundInfluentialQuantitative analyses reveal the importance of regulated Hdmx degradation for p53 activation
Wang, Y. V., Wade, M., Wong, E., Li, Y.-C., Rodewald, L. W., & Wahl, G. M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701497104 · Cited by 116 · see citing works
Ubiquitin becomes ubiquitous in cancer
Shi, D., & Grossman, S. R. (2010) · Cancer Biology & Therapy · doi:10.4161/cbt.10.8.13417 · Cited by 118 · see citing works
Human protein–protein interaction networks and the value for drug discovery
Ruffner, H., Bauer, A., & Bouwmeester, T. (2007) · Drug Discovery Today · doi:10.1016/j.drudis.2007.07.011 · Cited by 116 · see citing works
Ma, H., Chen, H., Guo, X., Wang, Z., Sowa, M. E., Zheng, L., Hu, S., Zeng, P.-Y., Guo, R., Diao, J., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1116349109 · Cited by 117 · see citing works
14‐3‐3γ binds to MDMX that is phosphorylated by UV‐activated Chk1, resulting in p53 activation
Jin, Y., Dai, M., Lu, S. Z., Xu, Y., Luo, Z., Zhao, Y., & Lu, H. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601010 · Cited by 113 · see citing works
Saha, A., Murakami, M., Kumar, P., Bajaj, B. G., Sims, K., & Robertson, E. S. (2009) · Journal of Virology · doi:10.1128/jvi.02408-08 · Cited by 114 · see citing works
Mdm2 and MdmX partner to regulate p53
Wang, X., & Jiang, X. (2012) · FEBS Letters · doi:10.1016/j.febslet.2012.02.049 · Cited by 111 · see citing works
Modulation of the p53/MDM2 interplay by HAUSP inhibitors
Tavana, O., & Gu, W. J. (2016) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjw049 · Cited by 108 · see citing works
Regulation of the p53-MDM2 pathway by 14-3-3 σ and other proteins
Lee, M., & Lozano, G. (2006) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2006.03.009 · Cited by 108 · see citing works
Deubiquitylating Enzymes in Cancer and Immunity
Ren, J., Yu, P., Liu, S., Li, R., Niu, X., Chen, Y., Zhang, Z., Zhou, F., & Zhang, L. (2023) · Advanced Science · doi:10.1002/advs.202303807 · Cited by 107 · see citing works
Yang, W.-L., Zhang, X., & Lin, H.-K. (2010) · Oncogene · doi:10.1038/onc.2010.190 · Cited by 101 · see citing works
MdmX is a substrate for the deubiquitinating enzyme USP2a
Allende-Vega, N., Sparks, A., Lane, D. P., & Saville, M. K. (2010) · Oncogene · doi:10.1038/onc.2009.330 · Cited by 100 · see citing works
MYC Is Activated by USP2a-Mediated Modulation of MicroRNAs in Prostate Cancer
Benassi, B., Flavin, R., Marchionni, L., Zanata, S. M., Pan, Y., Chowdhury, D., Marani, M., Strano, S., Muti, P. C., Blandino, G., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0219 · Cited by 100 · see citing works
Reverse the curse—the role of deubiquitination in cell cycle control
Song, L., & Rapé, M. (2008) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2008.01.012 · Cited by 100 · see citing works
Fernández‐Montalván, A., Bouwmeester, T., Joberty, G., Mader, R., Mahnke, M., Pierrat, B., Schlaeppi, J., Worpenberg, S., & Gerhartz, B. (2007) · The FEBS Journal · doi:10.1111/j.1742-4658.2007.05952.x · Cited by 96 · see citing works
Regulation of USP7: A High Incidence of E3 Complexes
Kim, R. Q., & Sixma, T. K. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.05.028 · Cited by 96 · see citing works
Edelmann, M. J., Nicholson, B., & Kessler, B. M. (2011) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399411002031 · Cited by 97 · see citing works
Differential Roles of ATM- and Chk2-Mediated Phosphorylations of Hdmx in Response to DNA Damage
Pereg, Y., Lam, S., Teunisse, A., Biton, S., Meulmeester, E., Mittelman, L., Buscemi, G., Okamoto, K., Taya, Y., Shiloh, Y., et al. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00562-06 · Cited by 93 · see citing works
Self-citationThe Regulation of the p53-mediated Stress Response by MDM2 and MDM4Preprint
Perry, M. E. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a000968 · Cited by 92 · see citing works
Deubiquitylating Enzymes and DNA Damage Response Pathways
Jacq, X., Kemp, M. I., Martin, N. M. B., & Jackson, S. P. (2013) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-013-9635-3 · Cited by 90 · see citing works
Xu, P., Xiao, H., Yang, Q., Hu, R., Lianyong, J., Bi, R., Jiang, X., Wang, L., Mei, J., Ding, F., et al. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-019-0356-6 · Cited by 86 · see citing works
Roberts, A. M., Watson, I. R., Evans, A. J., Foster, D. A., Irwin, M. S., & Ohh, M. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-1770 · Cited by 88 · see citing works
USP7 deubiquitinase promotes ubiquitin-dependent DNA damage signaling by stabilizing RNF168.
Zhu, Q., Sharma, N., He, J., Wani, G., & Wani, A. A. (2015) · Cell Cycle · doi:10.1080/15384101.2015.1007785 · Cited by 87 · see citing works
He, J., Zhu, Q., Wani, G., Sharma, N., Han, C., Qian, J., Pentz, K., Wang, Q., & Wani, A. A. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.589812 · Cited by 87 · see citing works
Liu, H., Li, X., Ning, G., Zhu, S., Ma, X., Liu, X., Liu, C., Huang, M., Schmitt, I., Wüllner, U., et al. (2016) · PLoS Biology · doi:10.1371/journal.pbio.2000733 · Cited by 86 · see citing works
Roles of HAUSP-mediated p53 regulation in central nervous system development
Kon, N., Zhong, J., Kobayashi, Y., Li, M., Szabolcs, M., Ludwig, T., Canoll, P. D., & Gu, W. (2011) · Cell Death & Differentiation · doi:10.1038/cdd.2011.12 · Cited by 79 · see citing works
Deubiquitination of Tip60 by USP7 determines the activity of the p53-dependent apoptotic pathway.
Dar, A., Shibata, E., & Dutta, A. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.00358-13 · Cited by 83 · see citing works
Zhao, G., Lin, Z., Lu, C., Gu, J., Yuan, Y., Xu, F., Liu, R., Ge, D., & Ding, J. (2014) · Tumor Biology · doi:10.1007/s13277-014-2773-4 · Cited by 84 · see citing works
Kessler, B. M., & Edelmann, M. J. (2011) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-011-9176-6 · Cited by 83 · see citing works
Balance of Yin and Yang: Ubiquitylation-Mediated Regulation of p53 and c-Myc
Dai, M., Jin, Y., Gallegos, J. R., & Lu, H. (2006) · Neoplasia · doi:10.1593/neo.06334 · Cited by 83 · see citing works
MDMX (MDM4), a Promising Target for p53 Reactivation Therapy and BeyondPreprint
Marine, J., & Jochemsen, A. G. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026237 · Cited by 81 · see citing works
Self-citationBilateral inhibition of HAUSP deubiquitinase by a viral interferon regulatory factor protein
Lee, H.-R., Choi, W., Lee, S., Hwang, J., Hwang, E., Guchhait, K., Haas, J., Tóth, Z., Jeon, Y. H., Oh, T.-K., et al. (2011) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2142 · Cited by 81 · see citing works
Phosphorylation of MDMX Mediated by Akt Leads to Stabilization and Induces 14-3-3 Binding
Lopez-Pajares, V., Kim, M. M., & Yuan, Z.-M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m710030200 · Cited by 79 · see citing works
- Authors
- Meulmeester, E., Maurice, M. M., Boutell, C., Teunisse, A. F. A. S., Ovaa, H., Abraham, T. E., Dirks, R. W., & Jochemsen, A. G.
- Affiliations
- Leiden University Medical Center (NL)
- Hubrecht Institute for Developmental Biology and Stem Cell Research (NL)
- The Netherlands Cancer Institute (NL)
- Corresponding author
- Jochemsen, Aart G.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2005-05
- Volume
- 18
- Issue
- 5
- Pages
- 565-576
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2057061154
- Cited by
- 260
- References
- 37
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 3 · 2020: 13 · 2019: 10 · 2018: 5 · 2017: 8 · 2016: 14 · 2015: 12 · 2014: 11 · 2013: 18 · 2012: 18
- FWCI
- 6.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- USP7, HDMX, MDM2, p53, deubiquitination, protein stability, DNA damage response, ubiquitin-proteasome system, p53 tumor suppressor, protein degradation, ubiquitin ligase
- MeSH terms
- Ubiquitin-Specific Peptidase 7, Animals, Carrier Proteins, Cell Line, DNA Damage, Humans, Nuclear Proteins, Endopeptidases, Proto-Oncogene Proteins, Tumor Suppressor Protein p53, Cell Cycle Proteins, Protein Isoforms, Ubiquitin, Ubiquitin Thiolesterase, Intracellular Signaling Peptides and Proteins, Mice, Proto-Oncogene Proteins c-mdm2
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