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Cited by 50Cancer-related Molecular PathwaysUbiquitin and proteasome pathwaysHeat shock proteins research

Nuclear and cytoplasmic degradation of endogenous p53 and HDM2 occurs during down-regulation of the p53 response after multiple types of DNA damage

Joseph, Troy W., Zaika, Alex, Moll, Ute M.·2003·The FASEB Journal
DOI 10.1096/fj.02-0931com
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Abstract

The principal regulator of p53 stability is HDM2, an E3 ligase mediating p53 degradation via the ubiquitin-26S proteasome pathway. Until recently, the accepted model held that p53 degradation occurs exclusively on cytoplasmic proteasomes, with an absolute requirement for nuclear export of p53 via the CRM1 pathway. However, 26S proteasomes are abundant in cytosol and nucleus. Using forced overexpression of HDM2 in mutant p53 tumor cells, we previously found that p53 degradation occurs in both the nucleus and the cytoplasm. p53 null cells coexpressing export-defective p53 and HDM2 retained partial competence for p53 degradation, challenging the obligatory export model. Because the ability of local nuclear destruction might add important control in switching off the p53 pathway, we now test this notion for physiological situations in untransfected cells and determine the significance of this regulation. Despite nuclear export blockade by leptomycin B and HTLV1-Rex protein, two potent CRM1 inhibitors, nuclear degradation of endogenous wild-type p53 and HDM2 occurs during down-regulation of the p53 response. This was seen in RKO and U2OS cells recovering from all major forms of DNA damage, including UV, gamma-IR, camptothecin, or cisplatinum. Moreover, significant nuclear degradation of endogenous p53 and HDM2 occurs in isolated nuclear fractions prepared from these recovering cells. Furthermore, nuclear proteasomes efficiently degrade ubiquitinated p53 in vitro. Our data indicate that in nonlethal outcomes of cellular stress, when DNA damage has been successfully repaired and the active p53 response needs to be down-regulated quickly to resume normal homeostasis, both nuclear and cytoplasmic proteasomes are recruited to efficiently degrade the elevated p53 and HDM2 protein levels. The physiological significance of local nuclear destruction lies in the fact that it adds tighter control and speed to switching the p53 pathway off.

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  • Proteasome-dependent degradation of nuclear p53 can also effectively prevent its transactivation function, suggesting that monoubiquitylation of cytoplasmic p53 is required for other processes.

    “However, proteasome-dependent degradation of nuclear p53 can also effectively prevent its transactivation function [111,112], suggesting monoubiquitylation of cytoplasmic p53 is required for other processes.”

    From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [112]

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Authors
Joseph, T. W., Zaika, A., & Moll, U. M.
Affiliations
State University of New York (US)
ORCID
Moll, Ute M.
Venue
The FASEB Journal
Publisher
Wiley
Published
2003-09
Volume
17
Issue
12
Pages
1622-1630
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
DOI
10.1096/fj.02-0931com
OpenAlex
W2048410022
Cited by
50
References
28
Citations by year
2026: 1 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 1 · 2020: 3 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 2 · 2013: 2
FWCI
2.39
Type
journal article
Language
en
Open access
closed
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The FASEB Journal (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (T32CA009176, T32 CA09176-24)
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
p53 degradation, MDM2, nuclear proteasome, CRM1 nuclear export, DNA damage response, leptomycin B, UV damage, gamma irradiation, camptothecin, cisplatin, DNA repair, tumor suppressor regulation
MeSH terms
Cell Nucleus, Cysteine Endopeptidases, Cytoplasm, DNA Damage, Humans, Multienzyme Complexes, Nuclear Proteins, Proto-Oncogene Proteins, Tumor Cells, Cultured, Ubiquitins, Down-Regulation, Tumor Suppressor Protein p53, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-mdm2

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