The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
Different effects of p14ARF on the levels of ubiquitinated p53 and Mdm2 in vivo
Abstract
Mdm2 has been shown to promote its own ubiquitination and the ubiquitination of the p53 tumour suppressor by virtue of its E3 ubiquitin ligase activity. This modification targets Mdm2 and p53 for degradation by the proteasome. The p14ARF tumour suppressor has been shown to inhibit degradation of p53 mediated by Mdm2. Several models have been proposed to explain this effect of p14ARF. Here we have compared the effects of p14ARF overexpression on the in vivo ubiquitination of p53 and Mdm2. We report that the inhibition of the Mdm2-mediated degradation of p53 by p14ARF is associated with a decrease in the proportion of ubiquitinated p53. The levels of polyubiquitinated p53 decreased preferentially compared to monoubiquitinated species. p14ARF overexpression increased the levels of Mdm2 but it did not reduce the overall levels of ubiquitinated Mdm2 in vivo. This is unexpected because p14ARF has been reported to inhibit the ubiquitination of Mdm2 in vitro. In addition we show that like p14ARF, the proteasome inhibitor MG132 can promote the accumulation of Mdm2 in the nucleolus and that this can occur in the absence of p14ARF expression. We also show that the mutation of the nucleolar localization signal of Mdm2 does not impair the overall ubiquitination of Mdm2 but is necessary for the effective polyubiquitination of p53. These studies reveal important differences in the regulation of the stability of p53 and of Mdm2.
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“p14ARF inhibits the poly-ubiquitylation of p53 while the ubiquitylation of Mdm2 is unaffected (Xirodimas et al., 2001).”
From Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms (2001) · cites this paper as Xirodimas et al., 2001
In the citing paper
“While p14ARF also stabilizes Mdm2 and blocks Mdm2-mediated degradation of p53, its effects on p53 and Mdm2 ubiquitylation are the opposite of Mdmx.”
From Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms (2001) · cites this paper as Xirodimas et al., 2001
Citations
Cites
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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
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 · cited 1×
“Interaction of p53 with Mdm2 results in a dramatic reduction of the p53 levels in vivo (Haupt et al., 1997; Kubbutat et al., 1997; Bottger et al., 1997).”
Backgroundp53: puzzle and paradigm.Preprint
Ko, L. J., & Prives, C. L. (1996) · Genes & Development · doi:10.1101/gad.10.9.1054 · Cited by 2,346
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
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The ubiquitin–proteasome pathway: on protein death and cell life
Ciechanover, A. J. (1998) · The EMBO Journal · doi:10.1093/emboj/17.24.7151 · Cited by 1,419
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Research works printed but not linked: 1
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Andersen, J., Lyon, C. E., Fox, A. H., Leung, A. K. L., Lam, Y. W., Steen, H., Mann, M., & Lamond, A. I. (2002) · Current Biology · doi:10.1016/s0960-9822(01)00650-9 · Cited by 1,024
Hydrogen peroxide sensing, signaling and regulation of transcription factors
Marinho, H. S., Real, C., Cyrne, L., Soares, H., & Antunes, F. (2014) · Redox Biology · doi:10.1016/j.redox.2014.02.006 · Cited by 872
The p53–Mdm2 module and the ubiquitin system
Michael, D., & Oren, M. (2002) · Seminars in Cancer Biology · doi:10.1016/s1044-579x(02)00099-8 · Cited by 772
Regulation of HDM2 activity by the ribosomal protein L11
Lohrum, M. A. E., Ludwig, R. L., Kubbutat, M. H. G., Hanlon, M., & Vousden, K. H. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00134-x · Cited by 626
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Metadata
- Authors
- Xirodimas, D., Saville, M. K., Edling, C., Lane, D. P., & Laín, S.
- Affiliations
- University of Dundee (GB)
- Venue
- Oncogene
- Published
- 2001-08-16
- Volume
- 20
- Issue
- 36
- Pages
- 4972-4983
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2050259175
- Cited by
- 169
- References
- 37
- Citations by year
- 2024: 2 · 2023: 1 · 2021: 4 · 2020: 2 · 2019: 6 · 2018: 6 · 2017: 5 · 2016: 3 · 2015: 5 · 2014: 6 · 2013: 6 · 2012: 9
- FWCI
- 5.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- HAL (submittedVersion)
- 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
- p14ARF, p53, MDM2, ubiquitination, polyubiquitination, monoubiquitination, proteasomal degradation, E3 ubiquitin ligase, protein stability, nucleolar localization signal, MG132, tumor suppressor regulation
- MeSH terms
- Animals, Cell Line, Cell Nucleolus, Cysteine Endopeptidases, Leupeptins, Multienzyme Complexes, Nuclear Proteins, Proteins, Proto-Oncogene Proteins, Transfection, Ubiquitins, Cysteine Proteinase Inhibitors, Tumor Suppressor Protein p53, Tumor Suppressor Protein p14ARF, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-mdm2
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