Stress-mediated nuclear stabilization of p53 is regulated by ubiquitination and importin-α3 binding
Open accessAbstract
The activity of p53 as an inducible transcription factor depends on its rapid nuclear stabilization after stress. However, surprisingly, mechanism(s) that regulate nuclear p53 accumulation are not well understood. The current model of stress-induced nuclear accumulation holds that a decrease in p53 nuclear export leads to its nuclear stabilization. We show here that regulated nuclear import of p53 also has a critical function. p53 import is mediated by binding to the importin-alpha3 adapter and is negatively regulated by ubiquitination. p53 harbors several nuclear localization signals (NLS), with the major NLS I located at amino-acids 305-322. We find that direct binding of p53 to importin-alpha3 depends on the positive charge contributed by lysine residues 319-321 within NLS I. The same lysines are also targets of MDM2-mediated ubiquitination. p53 ubiquitination occurs primarily in unstressed cells, but decreases dramatically after stress. Importin-alpha3 preferentially interacts with non-ubiquitinated p53. Thus, under normal growth conditions, ubiquitination of Lys 319-321 negatively regulates p53-importin-alpha3 binding, thereby restraining p53 import. Conversely, stress-induced accumulation of non-ubiquitinated p53 in the cytoplasm promotes interaction with importin-alpha3 and rapid import. In later phases of the stress response, blocked nuclear export also takes effect. We propose that p53 nuclear import defines an important novel level of regulation in the p53-mediated stress response.
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p53 activation can be enhanced by reduced nuclear export and increased nuclear import.
“Conversely, p53 activation can be enhanced by reduced nuclear export and increased nuclear import [6,7].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [7]
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- Authors
- Marchenko, N. D., Hanel, W., Li, D., Becker, K., Reich, N., & Moll, U. M.
- Affiliations
- Stony Brook University (US)
- Corresponding author
- Marchenko, N D
- Venue
- Cell Death & Differentiation
- Published
- 2009-11-20
- Volume
- 17
- Issue
- 2
- Pages
- 255-267
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC4419752
- OpenAlex
- W2089848839
- Cited by
- 123
- References
- 43
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 4 · 2023: 13 · 2022: 8 · 2021: 11 · 2020: 8 · 2019: 5 · 2018: 4 · 2017: 9 · 2016: 6 · 2015: 8 · 2014: 6 · 2013: 6 · 2012: 10
- FWCI
- 3.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- GRO (submittedVersion, cc-by)
- Funders
- National Cancer Institute (R01 CA60664, R01CA060664, R01CA093853)
- National Institute of General Medical Sciences (T32GM008444)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- p53, nuclear import, importin alpha3, ubiquitination, MDM2, nuclear localization signal, stress response, lysine residues, nuclear export, transcription factor regulation
- MeSH terms
- Adenocarcinoma, Cell Division, Cell Nucleus, Colonic Neoplasms, Cytoplasm, Humans, Lung Neoplasms, Lysine, Protein Binding, Stress, Physiological, Tumor Suppressor Protein p53, Active Transport, Cell Nucleus, alpha Karyopherins, HCT116 Cells, Proto-Oncogene Proteins c-mdm2, Ubiquitination
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