The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53
Open accessAbstract
The RING finger proteins HdmX and Hdm2 share significant structural and functional similarity. Hdm2 is a member of the RING finger family of ubiquitin-protein ligases E3 and targets the tumor suppressor protein p53 for degradation. Although HdmX also binds to p53, HdmX does not induce p53 degradation. Moreover, HdmX has been reported to interfere with p53 degradation in overexpression experiments. To obtain insight into the mechanism by which HdmX interferes with p53 degradation, we studied the effect of HdmX on the E3 activity of Hdm2 in vitro. Surprisingly, this revealed that HdmX stimulates Hdm2-mediated ubiquitination of p53 and that HdmX facilitates ubiquitination of Hdm2 and vice versa. In addition, down-regulation of HdmX expression within cells results in the accumulation of both p53 and Hdm2. Because HdmX alone does not have appreciable E3 activity, these data indicate that HdmX acts as a stimulator, rather than as an inhibitor, of the E3 activity of Hdm2 and that, at least under certain conditions, HdmX is actively involved in the degradation of both p53 and Hdm2.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Mdm4 further contributes to Mdm2 stability by disrupting self-ubiquitination of the latter (Stad et al., 2001), while also stimulating Mdm2-mediated polyubiquitination of p53 (Linares et al., 2003).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Linares et al., 2003
In the citing paper
“Despite conservation of the C2H2C4 RING domain, Mdmx shows little intrinsic ubiquitin ligase activity towards p53 [10].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [10]
In the citing paper
“Together with the observation that the Mdm2–Mdmx hetero-oligomer is a more effective ligase for p53 in vitro than Mdm2 alone [10], this has led to a model in which the Mdm2–Mdmx ligase complex is more efficient in targeting p53 for ubiquitylation and degradation.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [10]
In the citing paper
“By contrast, MDMX does not homo-oligomerize and has no intrinsic ubiquitin ligase function, although it can increase or decrease MDM2 ubiquitin ligase activity depending on MDMX abundance16.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [16]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells
Elbashir, S. M., Harborth, J., Lendeckel, W., Yalcin, A., Weber, K., & Tuschl, T. (2001) · Nature · doi:10.1038/35078107 · Cited by 9,456
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
The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction
Glickman, M. H., & Ciechanover, A. J. (2002) · Physiological Reviews · doi:10.1152/physrev.00027.2001 · Cited by 4,296
Self-citationRegulation 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
Live or let die: the cell's response to p53
Vousden, K. H., & Lü, X. (2002) · Nature reviews. Cancer · doi:10.1038/nrc864 · Cited by 3,231
Mechanisms Underlying Ubiquitination
Pickart, C. M. (2001) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.70.1.503 · Cited by 3,184
TAK1 is a ubiquitin-dependent kinase of MKK and IKK
Wang, C., Deng, L., Hong, M., Akkaraju, G. R., Inoue, J.-I., & Chen, Z. J. (2001) · Nature · doi:10.1038/35085597 · Cited by 2,125
Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
Honda, R., Tanaka, H., & Yasuda, H. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01480-4 · Cited by 1,951
Recognition of the polyubiquitin proteolytic signal
Thrower, J. S., Hoffman, L. M., Rechsteiner, M., & Pickart, C. M. (2000) · The EMBO Journal · doi:10.1093/emboj/19.1.94 · Cited by 1,769
Themes and variations on ubiquitylation
Weissman, A. M. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35056563 · Cited by 1,507
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
Mdm2 Is a RING Finger-dependent Ubiquitin Protein Ligase for Itself and p53
Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H., & Weissman, A. M. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.8945 · Cited by 1,044
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
Hashizume, R., Fukuda, M., Maeda, I., Nishikawa, H., Oyake, D., Yabuki, Y., Ogata, H., & Ohta, T. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.c000881200 · Cited by 634
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
Structure of a BRCA1-BARD1 heterodimeric RING-RING complex.
Brzović, P. S., Rajagopal, P., Hoyt, D. W., King, M., & Klevit, R. E. (2001) · Nature Structural Biology · doi:10.1038/nsb1001-833 · Cited by 511
Pickart, C. M. (2000) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(00)01681-9 · Cited by 458
Cell Cycle–Regulated Modification of the Ribosome by a Variant Multiubiquitin Chain
Spence, J. L., Gali, R. R., Dittmar, G., Sherman, F., Karin, M., & Finley, D. J. (2000) · Cell · doi:10.1016/s0092-8674(00)00011-8 · Cited by 382
Honda, R., & Yasuda, H. (2000) · Oncogene · doi:10.1038/sj.onc.1203464 · Cited by 376
MDM2 interacts with MDMX through their RING finger domains
Tanimura, S., Ohtsuka, S., Mitsui, K., Shirouzu, K., Yoshimura, A., & Ohtsubo, M. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00254-9 · Cited by 324
The 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
Stabilization of the MDM2 Oncoprotein by Interaction with the Structurally Related MDMX Protein
Sharp, D. A., Kratowicz, S. A., Sank, M. J., & George, D. L. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.53.38189 · Cited by 286
Mutual Dependence of MDM2 and MDMX in Their Functional Inactivation of p53
Gu, J., Kawai, H., Nie, L., Kitao, H., Wiederschain, D., Jochemsen, A. G., Parant, J. M., Lozano, G., & Yuan, Z.-M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200150200 · Cited by 265
The BRCA1/BARD1 heterodimer, a tumor suppressor complex with ubiquitin E3 ligase activity
Baer, R. J. (2002) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(01)00269-6 · Cited by 263
Mdmx 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
p53-Mdm2--the affair that never ends
Alarcon-Vargas, D. (2002) · Carcinogenesis · doi:10.1093/carcin/23.4.541 · Cited by 234
Cell type‐specific inhibition of p53‐mediated apoptosis by mdm2.
Haupt, Y., Barak, Y., & Oren, M. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00504.x · Cited by 228
Autoubiquitination of the BRCA1·BARD1 RING Ubiquitin Ligase
Chen, A., Kleiman, F. E., Manley, J. L., Ouchi, T., & Pan, Z. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201252200 · Cited by 223
Hengstermann, A., Linares, L. K., Ciechanover, A. J., Whitaker, N. J., & Scheffner, M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.3.1218 · Cited by 212
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
Enhancement of BRCA1 E3 Ubiquitin Ligase Activity through Direct Interaction with the BARD1 Protein
Xia, Y., Pao, G. M., Chen, H.-W., Verma, I. M., & Hunter, T. R. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m204591200 · Cited by 199
Lai, Z., Ferry, K. V., Diamond, M. A., Wee, K. E., Kim, Y. B., Ma, J., Yang, T., Benfield, P. A., Copeland, R. A., & Auger, K. R. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m011517200 · Cited by 170
Nuber, U. A., Schwarz, S. E., Kaiser, P., Schneider, R., & Scheffner, M. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.5.2795 · Cited by 150
Self-citationAberrant 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 147
Stad, R., Ramos, Y. F. M., Little, N., Grivell, S., Attema, J., van der Eb, A. J., & Jochemsen, A. G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003496200 · Cited by 145
Activation of the Cell Death Program by Nitric Oxide Involves Inhibition of the Proteasome
Glockzin, S., von Knethen, A., Scheffner, M., & Brüne, B. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.28.19581 · Cited by 123
Self-citationMdmX Is a RING Finger Ubiquitin Ligase Capable of Synergistically Enhancing Mdm2 Ubiquitination
Badciong, J. C., & Haas, A. L. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208593200 · Cited by 108
Hengstermann, A., Whitaker, N. J., Zimmer, D., Zentgraf, H., & Scheffner, M. (1998) · Oncogene · doi:10.1038/sj.onc.1202282 · Cited by 32
Self-citation
Research works printed but not linked: 2
- Ramos, Y. F., Stad, R., Attema, J., Peltenburg, L. T., van der Eb, A. J. & Jochemsen, A. G. (2001) Cancer Res. 61, 1839–1842.11280734
- Xia, Y., Pao, G., Chen, H. W., Verma, I. M. & Hunter, T. (2002) J. Biol. Chem. 278, 5255–5263.12431996
Cited by
Sorted by citations
RING Domain E3 Ubiquitin Ligases
Deshaies, R. J., & Joazeiro, C. A. P. (2009) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.78.101807.093809 · Cited by 2,679
Malignant astrocytic glioma: genetics, biology, and paths to treatment
Furnari, F. B., Fenton, T., Bachoo, R. M., Mukasa, A., Stommel, J. M., Stegh, A., Hahn, W. C., Ligon, K. L., Louis, D. N., Brennan, C., et al. (2007) · Genes & Development · doi:10.1101/gad.1596707 · Cited by 2,316
The first 30 years of p53: growing ever more complex.
Levine, A. J., & Oren, M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2723 · Cited by 1,967
Kruse, J.-P., & Gu, W. (2009) · Cell · doi:10.1016/j.cell.2009.04.050 · Cited by 1,610
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
Metadata
- Authors
- Linares, L. K., Hengstermann, A., Ciechanover, A., Müller, S., & Scheffner, M.
- Affiliations
- Center for Biochemistry, Medical Faculty, and Center for Molecular Medicine, University of Cologne, Joseph-Stelzmann-Strasse 52, 50931 Cologne, Germany; and Department of Biochemistry and The Rappaport Family Institute for Research in the Medical Sciences, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel
- Technion – Israel Institute of Technology (IL)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-09-24
- Volume
- 100
- Issue
- 21
- Pages
- 12009-12014
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC218704
- OpenAlex
- W2046135777
- Cited by
- 361
- References
- 38
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 5 · 2023: 11 · 2022: 15 · 2021: 17 · 2020: 17 · 2019: 14 · 2018: 10 · 2017: 16 · 2016: 16 · 2015: 12 · 2014: 30 · 2013: 19 · 2012: 30
- FWCI
- 4.81
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- KOPS (University of Konstanz) (submittedVersion)
- Funders
- German-Israeli Foundation for Scientific Research and Development
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- HDMX, MDM2, p53 degradation, ubiquitination, E3 ubiquitin ligase, RING finger protein, protein degradation, tumor suppressor, protein-protein interaction, p53 accumulation
- MeSH terms
- Amino Acid Sequence, Base Sequence, Cell Line, Humans, Molecular Sequence Data, Nuclear Proteins, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Transfection, Tumor Suppressor Protein p53, Ubiquitin, RNA, Small Interfering, Ubiquitin-Protein Ligases, Proto-Oncogene Proteins c-mdm2, In Vitro Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
