Quantitative analyses reveal the importance of regulated Hdmx degradation for p53 activation
Open accessAbstract
P53 regulates numerous downstream targets to induce cell cycle arrest, senescence, apoptosis, and DNA repair in response to diverse stresses. Hdm2 and Hdmx are critical negative regulators of P53 because Hdm2 regulates P53 abundance, and both can antagonize P53 transactivation. Modest changes in Hdm2 or Hdmx abundance affect P53 regulation, yet quantitative information regarding their endogenous intracellular concentrations and subcellular distributions during a stress response are lacking. We analyzed these parameters in normal and cancer cells after DNA damage. Our data show that the nuclear abundance of Hdm2 and Hdmx relative to P53 limits P53 activity in cells growing in culture. Upon DNA damage, P53 nuclear abundance increases, whereas Hdm2 and Hdmx stability decreases, which greatly limits their ability to antagonize P53, regardless of their levels. These data indicate that the damage-activated switch in Hdm2 ubiquitin ligase preference from P53 to itself and Hdmx is central to P53 activation.
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Mdm2 and Mdmx are most abundant in the cytosol in many cell lines, suggesting that cytoplasmic localization is important for their function.
“However, Mdm2 and Mdmx are most abundant in the cytosol in many cell lines, suggesting cytoplasmic localization is important for their function [3].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [3]
Modifications caused by damage help activate p53 by shifting the balance of the pathway and changing how tightly Mdm2 and Mdmx bind p53.
“The increasing ratio between p53 and its negative regulators, concomitant with the onset of p53 transcriptional activity, suggests that damage-induced modifications contribute to p53 activation by changing the stoichiometry of the pathway, and altering the affinity of Mdm2 and Mdmx for p53 [3].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [3]
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- Authors
- Wang, Y. V., Wade, M., Wong, E., Li, Y.-C., Rodewald, L. W., & Wahl, G. M.
- Affiliations
- Salk Institute for Biological Studies (US)
- Institute of Molecular and Cell Biology (SG)
- *Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037; and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-07-24
- Volume
- 104
- Issue
- 30
- Pages
- 12365-12370
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1941475
- OpenAlex
- W1984104797
- Cited by
- 116
- References
- 49
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 2 · 2020: 10 · 2019: 5 · 2018: 3 · 2017: 5 · 2016: 7 · 2015: 3 · 2014: 10 · 2013: 8 · 2012: 10
- FWCI
- 5.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Universiteit Leiden
- National Cancer Institute (CA61449, R01CA100845, CA 100845, R01CA061449)
- 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 activation, HDMX, MDM2, protein degradation, DNA damage response, protein stability, cancer cells
- MeSH terms
- Cell Line, DNA, DNA Damage, Gene Expression Regulation, Humans, Kinetics, Nuclear Proteins, Protein Binding, Proto-Oncogene Proteins, Transcriptional Activation, Tumor Suppressor Protein p53, Cell Cycle Proteins
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