The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
MDM2 Promotes Ubiquitination and Degradation of MDMX
Open accessAbstract
The p53 tumor suppressor is regulated by MDM2-mediated ubiquitination and degradation. Mitogenic signals activate p53 by induction of ARF expression, which inhibits p53 ubiquitination by MDM2. Recent studies showed that the MDM2 homolog MDMX is also an important regulator of p53. We present evidence that MDM2 promotes MDMX ubiquitination and degradation by the proteasomes. This effect is stimulated by ARF and correlates with the ability of ARF to bind MDM2. Promotion of MDM2-mediated MDMX ubiquitination requires the N-terminal domain of ARF, which normally inhibits MDM2 ubiquitination of p53. An intact RING domain of MDM2 is also required, both to interact with MDMX and to provide E3 ligase function. Increase of MDM2 and ARF levels by DNA damage, recombinant ARF adenovirus infection, or inducible MDM2 expression leads to proteasome-mediated down-regulation of MDMX levels. Therefore, MDMX and MDM2 are coordinately regulated by stress signals. The ARF tumor suppressor differentially regulates the ability of MDM2 to promote p53 and MDMX ubiquitination and activates p53 by targeting both members of the MDM2 family.
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“However, in addition to degrading p53, Mdm2 also undergoes auto-degradation [12,13] and targets Mdmx for degradation [14–16], which is critical for optimal p53 activation after stress.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [16]
In the citing paper
“MDMX and MDM2 form heterodimers through the C-terminal RING domains and the MDM2 RING domain alone is sufficient to degrade MDMX (Sharp et al, 1999;Tanimura et al, 1999;Pan and Chen, 2003).”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Pan and Chen, 2003
In the citing paper
“Several reports showed that MDMX can be ubiquitinated and degraded by MDM2 (De Graaf et al, 2003;Kawai et al, 2003;Pan and Chen, 2003).”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Pan and Chen, 2003
In the citing paper
“DNA damage induced by ionizing irradiation also promotes MDMX nuclear translocation and degradation by the proteasomes (Li et al, 2002;Pan and Chen, 2003).”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Pan and Chen, 2003
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Citations
Cites
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Mdm2 Is a RING Finger-dependent Ubiquitin Protein Ligase for Itself and p53
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Cited by
Sorted by citations
Awakening guardian angels: drugging the p53 pathway
Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R., & Lane, D. P. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2763 · Cited by 881
“Another consequence of MDM2–MDM4 heterodimerization is that MDM4 can be ubiquitylated by MDM2and is consequently degrade”
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Coping with stress: multiple ways to activate p53
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“…(Sharp et al., 1999; Tanimura et al., 1999), which results in the stabilization of Mdm2 (Stad et al., 2001; Gu et al., 2002) or the Mdm2-mediated degradation of MdmX (de Graaf et al., 2003; Kawai et al., 2003; Pan and Chen, 2003), depending on the relative expression levels of the two proteins.”
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Metadata
- Authors
- Pan, Y., & Chen, J.
- Affiliations
- Moffitt Cancer Center (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2003-08-01
- Volume
- 23
- Issue
- 15
- Pages
- 5113-5121
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC165735
- OpenAlex
- W2143351237
- Cited by
- 246
- References
- 33
- Citations by year
- 2025: 5 · 2024: 3 · 2023: 9 · 2022: 9 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 4 · 2017: 9 · 2016: 15 · 2015: 13 · 2014: 16 · 2013: 8 · 2012: 17
- FWCI
- 4.79
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Cancer Society
- National Institutes of Health
- 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
- MDM2, MDMX, p53, ARF, ubiquitination, proteasomal degradation, RING domain, E3 ubiquitin ligase, DNA damage response, tumor suppressor regulation, p53 activation
- MeSH terms
- Amino Acid Sequence, Epitopes, Cysteine Endopeptidases, DNA Damage, Humans, Models, Biological, Molecular Sequence Data, Multienzyme Complexes, Nuclear Proteins, Plasmids, Protein Binding, Proto-Oncogene Proteins, Transfection, Tumor Cells, Cultured, Blotting, Western, Signal Transduction, Down-Regulation, Tumor Suppressor Protein p53, Apoptosis, Protein Structure, Tertiary, Ubiquitin, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-mdm2
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